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University of Southern California Dissertations and Theses
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Let there be LIGHT: TNFSF14 immunomodulating properties for cancer immunotherapy
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Let there be LIGHT: TNFSF14 immunomodulating properties for cancer immunotherapy
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Content
LET THERE BE LIGHT: TNFSF14 IMMUNOMODULATING PROPERTIES
FOR CANCER IMMUNOTHERAPY
By Mikk Otsmaa
A Thesis Presented to
THE FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements of the Degree
MASTER OF SCIENCE
MOLECULAR MICROBIOLOGY AND IMMUNOLOGY
August 15, 2019
2
Acknowledgments
I would like to thank my principal investigator Dr. Martin Kast, for without whom none of this would be possible.
His mentorship and constant encouragement in my abilities allowed me to mature from a novice to Master of
Science. My student mentor, Joseph Skeate deserves special thanks. His instruction and oversight on my
laboratory experience was a paramount element in me becoming a better student, scientist, and individual.
Further thanks are necessary for my thesis committee members Dr. Weiming Yuan and Dr. Francis Markland.
Their agreement to oversee my thesis dissertation has allowed me to demonstrate my understanding of cancer
immunology the likes of which I have never done before.
My family marks the biggest influence of my success. Thank you Ema, Isa, and Kai for always supporting me
during my achievements and stresses. I love you, and I am forever grateful. Finally, I would like to thank my
grandmother Helge for allowing me into her home while I attended my Master’s program. Her attentive care,
wit, and affection helped teach me what family and responsibility require.
3
List of Abbreviations
Ad Adenovirus
BTLA B and T Lymphocyte Attenuator
CTLA-4 Cytotoxic T Lymphocyte Antigen-4
DC Dendritic Cell
DcR3 [TR6] Decoy Receptor 3
EGFR Epidermal Growth Factor Receptor
GM-CSF Granulocyte-Macrophage Colony Stimulating Factor
HEV High Endothelial Venule
HVEM Herpes Virus Entry Mediator
ICAM Intracellular Adhesion Molecule
IFN Interferon
IL-1a Interleukin 1a
LIGHT [TNFSF14] Tumor Necrosis Factor Superfamily 14
HVEM Herpesvirus entry mediator
HPV Human Papillomavirus
LT R Lymphotoxin- Receptor
MAdCAM Mucosal Addressin Cell Adhesion Molecule
MDSC Myeloid Derived Suppressor Cell
MECA-79 PNAd marker
MIG [CXCL9] Monokine Induced by Gamma Interferon [Chemokine (C-X-C motif) ligand 9]
MIP-2 Macrophage Inflammatory Protein 2
MSC Bone Marrow-Derived Mesenchymal Stem Cells
NF B Nuclear Factor- B
NGR Vascular targeting peptide sequence CNCRCG
NK Natural Killer Cell
NKT Natural Killer T Cell
PD-1 Programmed Cell Death-1
PD-L1 Programmed Death Ligand-1
PNAd Peripheral Node Addressin, LT R dependent
scFv Single Chain Variable Fragment of an Immunoglobulin Protein
SLO Secondary Lymphoid Organ
TGF- Transforming Growth Factor
Th1 Helper T cell type 1
TME Tumor Microenvironment
TNF Tumor Necrosis Factor
TRAF TNF Receptor Associated Factor
TLS Tertiary Lymphoid Structure
VCAM Vascular Cell Adhesion Molecule
vSMC Vascular Smooth Muscle Cell
VTP Vascular Targeting Peptide
4
Table of Contents
ACKNOWLEDGMENTS 2
LIST OF ABBREVIATIONS 3
LIST OF FIGURES 5
ABSTRACT 6
I. INTRODUCTION 7
CANCER IMMUNOTHERAPY 7
TUMOR MICROENVIRONMENT 7
TUMOR NECROSIS FACTOR FAMILY 10
LIGHT 11
II. LIGHT RECEPTOR MEDIATED MECHANISM PATHWAYS 12
DECOY RECEPTOR 3 12
HERPES VIRUS ENTRY MEDIATOR 12
LYMPHOTOXIN RECEPTOR 13
III. LIGHT EFFECTS ON TUMORS 14
LIGHT SENSITIZES TUMORS TO IFN 14
NORMALIZING TUMOR ANGIOGENIC VESSELS 14
HIGH ENDOTHELIAL VENULES ALLOW INTRATUMORAL VIP ACCESS TO LYMPHOCYTES 15
TERTIARY LYMPHOID STRUCTURES 16
TUMOR DESTRUCTION & AMPLIFIED TUMOR SPECIFICITY 16
IV. LIGHT DELIVERY SYSTEMS 17
GENE TRANSFER OF LIGHT EXPRESSING TUMORS 18
ADENOVIRUS VECTORS 19
ADOPTIVE TRANSFER OF LIGHT EXPRESSING CELLS 19
ANTIBODY FUSION PROTEINS 20
VASCULAR TARGETING PEPTIDES 21
V. LIGHT COMBINATION THERAPIES 22
LIGHT + THERAPEUTIC VACCINATIONS 22
LIGHT + CHECKPOINT INHIBITORS 23
VI. FUTURE DIRECTIONS 24
VII. CONCLUSION 26
REFERENCES 27
5
List of Figures
Figure 1: Soluble LIGHT PyMOL Rendering 10
Table 1: Vascular Targeting Peptides in Relation to LIGHT Therapy 21
6
Abstract
The continuing need for novel cancer therapies has turned its gaze towards the tumor necrosis factor
superfamily member 14 (TNFSF 14), also known as LIGHT. LIGHT (homologous to lymphotoxins, exhibits
inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T cells) is a
pro-inflammatory costimulatory protein expressed on immature dendritic cells, activated natural killer cells, and
activated T cells. By eliciting robust anti-tumor responses via interferon mediated apoptosis, tumor angiogenic
vascular normalization, high endothelial venule formation, tertiary lymphoid structure formation, and immune
activation, LIGHT has piqued the interest of researchers over the past two decades. By delivering LIGHT properly
to tumors via gene transfer, Adenovirus vectors, adoptive transfer, antibodies, or vascular targeting peptides,
LIGHT has shown promise as a new candidate in cancer immunotherapy. This review will further clarify the
diverse effects, deliveries, and immunotherapeutic combinations LIGHT has to offer.
7
I. Introduction
Cancer Immunotherapy
Human cancers remain amongst the most significant medical challenges worldwide, accounting for 1 out
of every 6 deaths that occur in humans (1). In the United States it is estimated that 39% of people will develop
cancer, and given the aging population in the United States we can reasonably assume cancer incidence rates will
continue to climb (2). As such, the need for new therapies that target cancer remains the epicenter of medical
research. Compared to current standards of care such as chemotherapy, surgery, and radiation; immunotherapies
have brought to the table a new set of tools and strategies that have expanded on the scope of cancer treatment
options. The main goals of cancer immunotherapy can be broken down into three separate clades: generation of
de novo anti-cancer immune responses, bolstering/amplification of ongoing immune function, or the prevention
of cancers from shutting down/manipulating anti-tumor responses. Historically this has been a balancing act due
to the nature of cancers arising from cells that are normally thought of as ‘self’. One of the challenges is to design
an effective cancer immunotherapy that is specific in its function against cancer, but does not lead to breaking of
immune tolerance and systemic autoimmunity. Approaches towards immunotherapy include immune-activating
or immune-suppressing agents such as checkpoint inhibitors, engineered T cells, stem cells, cytokines, and
chemokines (3-7). Regardless of the approach, immunotherapy modalities face a challenging opponent that stands
in the way of them succeeding, the tumor microenvironment.
Tumor Microenvironment
The tumor microenvironment (TME) is best described as a “wound that never heals”. With chronic
inflammation and immune cell suppression, the TME is a set of heterogeneous physiological conditions that
cancers actively develop to aid in their progression (8). Due to their immunosuppressive nature, the TME
conditions are difficult to combat with many therapeutic methods that aim to induce anti-tumor lymphocyte
responses (9). Two principle aspects in the generation of a tumor microenvironment are tumors’ ability to create
immunosuppressive surroundings as well as a separate set of angiogenic blood vessels.
8
The TME can be both inflammatory and immunosuppressive (9). As tumors develop, partly through
chronic inflammation, they often promote the secretion of cytokines and chemokines such as IL-10, CCL2, and
CCL5 which are able to recruit tumor associated macrophages (TAM) (10). Although their differentiation is
plastic, TAM differentiate into M2 immunosuppressive cells is partly due to the increased IL-10 and low IL-12
concentrations in the TME (10). Such macrophages can recruit non-cytotoxic T cells such as T regulatory cells
(Treg) and type 2 helper T cells (Th2) via transforming growth factor (TGF- ), CCL17, and CCL22 secretion
(9, 10). TAM can also recruit naïve T cells via CCL18 (10). Within the preexisting immunosuppressive TME, the
naïve T cells will differentiate into immunosuppressing phenotypes, further perpetuating the immunosuppressive
cycle (9, 10). The TME is also able to recruit potent pro-tumor myeloid derived suppressor cells (MDSC) (11).
MDSC are undifferentiated myeloid cells (progenitors for macrophages, dendritic cells (DC), and granulocytes)
that can execute multiple tumorigenic functions, such as lowering DC antigen presentation, T cell activation, and
natural killer cell (NK) cytotoxicity (8, 11). Furthermore, MDSC are able to release arginase, reactive oxygen
species (ROS), IL-10, and express programmed cell death ligand 1 (PD-L1) to lower T effector cell responses
(11). PD-L1 is amongst the most important ligands for the immunoediting of cancer from immune responses.
Cancers are able to utilize non-redundant immune checkpoints to further inhibit T cell responses, most
notably via the PD-L1/PD-1 axis and cytotoxic T lymphocyte antigen 4 (CTLA-4) (5, 12). In the presence of
chronic inflammatory cytokine interferon (IFN ), tumors express PD-L1, which binds to programmed cell death
receptor 1 (PD-1) constitutively expressed on activated T cells (5, 13). Upon PD-1/PD-L1 interaction, T cell
exhaustion and anergy occurs, allowing for tumors to avoid immunogenic responses. Furthermore, activated
inflammatory T lymphocytes cells express immunosuppressor CTLA-4, which competes with CD28 to bind TCR
costimulatory agents CD80 and CD86 (5, 12, 14). In the vicinity of so many immunosuppressor cells, many
CTLA-4
+
T cells succumb to the immunosuppression of the TME. Due to the exploitation of such immune
checkpoints, several anti-CTLA-4 and anti-PD-1/PD-L1 checkpoint inhibiting antibodies are available on the
market and have deemed useful within the clinic (4, 12, 14). However, the efficacy of checkpoint blockades is
determined by the preexistence of anti-tumor lymphocytes, in which the TME can already avoid (15, 16). As
9
such, this highlights the need for additional immunotherapies to be developed. As the TME develops
immunosuppression via selective immune cell recruitment and maturation, it is also sustained by its own blood
supply.
Healthy vasculature allows constant blood flow, oxygen perfusion, and circulation of immune cells;
features all of which tumor vasculature lack (17). Rather than building de novo vascular structures to
accommodate increasing metabolic requirements, tumors are able to extend existing healthy blood vessels through
angiogenesis. This ad-hoc vascular development is, however, far less optimal. As tumor cells divide, hypoxic
pockets develop within the tumor mass. Tumor cells within these hypoxic zones respond by overexpressing pro-
angiogenic factors such as vascular endothelial growth factor (VEGF) to modify nearby stromal cells (endothelial
cells, pericytes, vascular smooth muscle cells, fibroblasts) (18, 19). With less perfusion and a transfigured vascular
basement membrane, tumor angiogenic vessels further increase hypoxia, immune suppression, and intratumoral
pressure to increase chances of metastasis (18). One would think the reasonable approach would be to block
angiogenic vascular formation, however time has shown for this not to be the case. Although multiple anti-VEGF
therapeutics are FDA approved such as bevacizumab, researchers have tempered their expectations and no longer
think of tumor angiogenesis as a purely VEGF-driven mechanism (20-22). Pivoting from anti-angiogenic drug
development, many researchers have shifted the schema towards reversing the pathogenic features of tumor
vasculature (23).
When the vasculature within a tumor is normalized towards a non-pathogenic phenotype it has been shown
to alleviate hypoxia and can improve almost all therapy options whether they are immunotherapy, radiotherapy,
or chemotherapies (24). In the context of immunotherapy, the decrease in intratumoral pressure, reperfusion of
the tumor, and ability of immune cells to attach to vasculature and enter tumor tissue are all beneficial for
increasing the odds of mounting an effective anti-tumor response. However, for an immunotherapy to be
successful it is becoming clear that a multi-faceted approach is needed that can both dampen the
immunosuppressive nature of the TME as well as drive effector responses. For this reason, increasing scrutiny
has been directed towards utilizing the Tumor Necrosis Factor Family of receptors and ligands.
10
Tumor Necrosis Factor Family
The immunomodulating properties of the Tumor Necrosis Factor (TNF) family make it a good
immunotherapy candidate. The TNF family is a broad range of immune regulating ligands and receptors with
functions including, but not limited to T cell costimulation and lymphoid organogenesis (25). Novel cancer
therapies have revolved around TNF receptor family members such as 4-1BB and OX40, due to their ability to
stimulate innate and adaptive inflammatory responses (26-28). When combined with -GalCer, a Natural Killer
T cell (NKT) adjuvant, agonistic anti 4-1BB antibodies were found to eradicate 50% of lymphomas in murine
E -Myc B cell lymphomas (27). Anti PD-1 immunotherapy combined with agonistic monoclonal antibodies that
target OX40 have been shown to ablate 60% of murine ID8 ovarian tumors (28). Each of these TNF family
members are being studied in clinical trials due to their therapeutic promise (29, 30). Nevertheless, there exists
another TNF family member with a more diverse ligand and effector profile. Tumor Necrosis Factor Superfamily
14 (TNFSF14), also known as LIGHT (Figure 1), has been found to be a promising cancer therapeutic due to its
ability to generate robust anti-tumor responses (31, 32). Before elaborating on LIGHT’s tumor effects, its biology
and signaling pathways have to be further illustrated.
Figure 1: Soluble LIGHT rendered by PyMOL (PDB: 4ENO). Amino acid sequence 96-240. Each monomer
colored in pink, blue, red. Active sites highlighted yellow, N termini highlighted green, C termini highlighted
white.
11
LIGHT
LIGHT (homologous to lymphotoxins, exhibits inducible expression and competes with Herpes Simplex
Virus glycoprotein D for HVEM, a receptor expressed by T cells), is a membrane bound and soluble protein
primarily expressed on activated T cells and immature DC cells (33, 34). Within the TNF family, LIGHT is an
immunostimulant that binds three receptors: Lymphotoxin- Receptor (LT R), Herpes Virus Entry Mediator
(HVEM), and Decoy Receptor 3 (DcR3 or TR6) (33, 35). Roughly 29kDa in size, LIGHT is located on
chromosome 19p13.3, and can function as both a soluble and cell-bound homotrimeric 29kD type II membrane
protein (33, 36). LIGHT stimulates T cell, NK cell, and DC activation, proliferation responses, as well as
lymphoid tissue formation via its A’-A” and D-E loop (35, 37). The autoimmune consequences of LIGHT
overexpression results in T cell loss of peripheral tolerance; which has several implications for disorders such as
inflammatory bowel disease, diabetes, asthma, graft versus host disease, and atherosclerosis (37-43). Due to its
profound immuno-stimulatory downstream effects, LIGHT has called attention to itself as a promising cancer
immunotherapy candidate over the past two decades. By specifically targeting LIGHT to tumors, researchers have
utilized LIGHT’s capabilities to initiate immune responses against cancer.
LIGHT is an important costimulatory agent primarily found on activated natural killer cells (NK),
immature dendritic cells (DC), and activated T cells (34, 44). LIGHT aids mature NK cells to release pro
inflammatory cytokines interferon gamma (IFN ) and Granulocyte Macrophage Colony Stimulating factor (GM-
CSF) (32). GM-CSF can further potentiate anti-tumor immunity by assisting in the priming of tumor-specific
lymphocytes (45). When expressed on immature DCs, LIGHT acts as a de facto maturation ligand for DC maturity
(32). DC maturation can trigger the release of pro-inflammatory cytokines IL-6, IL-12, and TNF as well as
increased antigen presentation (44). Such increases in antigen presentation and lymphocyte priming within tumors
allow LIGHT to provide further therapeutic effects of cytotoxic CD8
+
T cells (46). As a T cell co-stimulating
factor, LIGHT bolsters helper 1 T cell (Th1) mediated IFN and GM-CSF expression as well as cytotoxic CD8
+
T cell responses (44). With all the downstream immunomodulating effects LIGHT elicits, it is important to
12
understand that LIGHT mediates this activity via surface ligand-receptor pathways, and that the effects are
receptor, cell type, and conformation dependent.
II. LIGHT Receptor Mediated Mechanism Pathways
Ligand-receptor mediated signaling are critical to immune cell function. LIGHT (both soluble and
membrane bound) utilizes a classic ligand-receptor mediated pathway that has 3 known receptors: DcR3,
HVEM, and LT R.
Decoy Receptor 3
Decoy Receptor 3 (DcR3 or TR6) is a soluble protein that binds LIGHT as well as Fas ligand (47). Lacking
cytosolic domains, DcR3 is a functional inhibitor of LIGHT’s immunostimulatory effects (48). Although murine
models lack DcR3, DcR3 retains importance as a biomarker in inflammatory disease as well as several human
cancers such as those of the lung, colon, and liver (44, 49, 50). Because DcR3 is difficult to detect in healthy
individuals, its functional effects are studied in pathological over- or under-expressive capacities (48). Not much
is known of DcR3’s physiological functions, yet its association with LIGHT as an attenuator warrants further
study.
Herpes Virus Entry Mediator
HVEM is a significant binding partner for the T cell costimulatory effects of LIGHT and acts as an
infection target for herpes virus glycoprotein D (the function of which it was first named) (51). Expressed on
lymphocytes, NK cells, smooth muscle, and epithelium, HVEM serves as an important T cell costimulatory agent
with regards to activation, suppression, proliferation, and survival (32, 34, 52). HVEM can induce pro
inflammatory or inhibitory pathways via the TNF family and Ig membrane pathways via Lymphotoxin /LIGHT
or B and T lymphocyte attenuator (BTLA)/CD160 respectively (52-54). HVEM expressed on NK cells can be
stimulated by LIGHT to secrete IFN via TNF receptor associated factor 2 (TRAF2) mediated nuclear factor- B
13
(NF B) RelA/p50 mechanisms (25, 32, 51, 55). HVEM is necessary for LIGHT’s costimulatory effect of
activating and propagating T effector cells in a CD28 independent T cell to T cell manner (34). Such pro
inflammatory HVEM interactions help increase Th1 cytokine expression of IFN and GM-CSF. LIGHT-HVEM
mediated T cell costimulation as well as NK activation both play a vital role to reduce cancer burden (55).
However, the immunostimulatory effects of HVEM-LIGHT are modulated by the expression of BTLA, and all
of their interplay is essential to consider when studying HVEM-LIGHT interactions.
HVEM function is due to three parameters: conformation, ligand, and solubility of ligand. The
conformation of HVEM is dictated by its multiple cysteine rich domain binding sites and BTLA expression (52,
54). BTLA inhibits T cell proliferation, and when BTLA and HVEM are coexpressed, HVEM takes the cis
conformation and functionally inhibits soluble LIGHT activity (52). Only membrane bound LIGHT can overcome
the inhibitory activity of cis HVEM (25, 52). When BTLA and HVEM are not expressed on the same surface,
HVEM takes the trans conformation, which both membrane bound and soluble LIGHT can activate (52). Despite
the anti-tumor costimulatory effects of HVEM-LIGHT, LT R perhaps contains the most anti-tumor efficacy.
Lymphotoxin- Receptor
LT R is a principle receptor for LIGHT, and is necessary for the formation of lymphoid structures, tertiary
lymphoid structures, tumor vascular normalization, and tumor cell death (35, 56). LT R is found on the surface
of epithelial, stromal, and myeloid cells, but not lymphocytes (38). LT R activation on stromal cells leads to the
formation of tertiary lymphoid structures (TLS) partly by expressing naïve T cell as well as DC attractant CCL21
and IFN induced chemokines IP-10, as well as Monokine induced by IFN (MIG) (32). Such lymphoid organ
neogenesis is able to initiate anti-tumor responses as well as generate memory (57). LT R activation can also
induce tumor vascular normalization via upregulation of pericyte intracellular junction markers (17, 58, 59).
Furthermore, evidence supports macrophage bound LT R stimulates TGF- mediated vascular remodeling and
normalization through the PNAd pathway (58). By utilizing two NF B pathways, LT R is able to effect tumor
apoptosis in a myriad of manners (60). LIGHT-LT R stimulation mediates apoptosis signaling by internalization
14
and localization of TNF associated factors (TRAF) 2, 3, and 5 into perinuclear spaces and causing apoptosis via
the mitochondrial pathway (35, 61). The effects mediated by the LIGHT-LT R axis make it responsible for the
majority of LIGHT’s downstream anti-tumor effects when properly expressed or delivered to the TME.
III. LIGHT Effects on Tumors
Effectively delivering LIGHT to tumors can have profound effects on the TME. In addition to sensitizing
tumors to IFN mediated apoptosis via multiple pathways, LIGHT induces tumor vasculature normalization via
increasing pericyte contractility and endothelial activation, generates HEVs, helps form TLSs, promotes
antitumor CD8+ T cells to penetrate the tumor, and establishes anti-tumoral memory (31, 58, 59, 62).
LIGHT Sensitizes Tumors to IFN
LIGHT sensitizes tumors to IFN -mediated apoptosis in multiple models such as breast carcinomas, colon
carcinomas, and hepatocellular carcinomas (63-66). Studies show when transfected with LIGHT and treated with
IFN , tumors underwent apoptosis at a greater rate than LIGHT transfection alone (63, 66). The mechanisms
involved include the mitochondrial apoptosis pathway involving downregulation of Bcl-2 and Bcl-XL, while
simultaneously upregulating pro-apoptotic protein Bak to activate cleavage of execution protein caspase 3 and
caspase 9. Further evidence of LIGHT induced caspase 8 activation indicates the use of death receptor pathways
as well (64). Similar LIGHT- IFN mediated apoptosis mechanisms have been found in cells in diabetes cases
(37). These findings are in parallel with the evidence that LIGHT induces an autoimmune like response against
several tumor lines.
Normalizing Tumor Angiogenic Vessels
LIGHT-VTP (VTP discussed further in section IV) based therapies developed by Johansson-Percival et
al. were found to combat tumor angiogenesis not by destroying tumor stroma, but by reversing their pathogenic
effects in a process called vascular normalization (17, 58, 59). Although exact normalization mechanisms are
15
unknown, evidence has shown LIGHT-VTP can normalize blood vessels via increased expression of LT R
dependent pericyte contractile markers ICAM-1, VCAM-1, smooth muscle actin (SMA), calponin, and
caldesmon (17, 58, 59). Such contractile markers aid in reversing the role of angiogenesis in the TME.
Intratumoral macrophages activated by LIGHT were found to secrete TGF- , which induced to vascular smooth
muscle cell (vSMC) phenotype switching to increase adhesion in a Rho-kinase dependent manner (58). Although
TGF- helps generate Tregs, which can inhibit immune rejection, it is also responsible for the differentiation of
pericytes as well, explaining the increased pericyte contractile markers found by Johansson-Percival et al. (32,
67, 68). Because macrophage-secreted TGF- is released so closely to stromal cells in these scenarios, Johansson
et al. hypothesize that TGF- would not be able to diffuse too far and cause pro-tumor effects. LIGHT-VTP
driven vascular normalization was shown to improve pericyte and vSMC markers in murine pancreatic
insulinoma, murine breast cancer, murine glioblastoma, human glioblastoma, and human astrocytoma models
thus far (17, 58, 59). Inducing vasculature normalization aims to reverse hypoxia and increase circulating
lymphocytes to the intratumoral area, aiding any cancer therapy (18, 69).
High Endothelial Venules Allow Intratumoral VIP Access to Lymphocytes
LT R activation is responsible for creating High Endothelial Venules (HEVs), lymph node entrances for
lymphocytes (70). HEVs are lined with LT R dependent MAdCAM1 addressin as well as peripheral node
addressins (PNAd), which bind L-selectin on entering lymphocytes (59). HEVs increase the infiltration of
lymphocytes into tumoral spaces via the expression of chemokine CCL21, which attracts naive CCR7+
lymphocytes which can further combat the TME (70, 71). The presence of tumor infiltrating lymphocytes are
posited with better outcomes and prognoses in cancer models such as melanoma, breast, ovarian, colorectal, and
lung (72, 73). LIGHT-LT R dependent construction of HEVs are therefore clinically relevant, and have been
detected via MECA 79 (PNAd marker) in pancreatic, breast, and glioblastoma models (18). Such increases in
lymphoid penetration leads to other structural changes in the tumor microenvironment as well. Generating
16
increased inflammation within the tumor, the presence of HEVs in LIGHT therapy further aid the construction of
tertiary lymphoid structures.
Tertiary Lymphoid Structures
TLS (sometimes referred to in the literature as tertiary lymphoid organs), are a subset of lymphoid organs
that arise in sites of chronic inflammation and are associated with autoimmune diseases (74). TLS are similar to
secondary lymphoid organs (SLO) by compartmentalizing T and B cells similarly. Unlike SLOs, TLSs are not
encapsulated and lack afferent lymph vessels, allowing them to directly interact with external antigens and
cytokines within the immediate environment (32, 74). TLSs are formed in association with the overexpression of
lymphocyte and DC chemokines CCL21 and CCL19 as well as HEV markers MAdCAM1 and PNAd: all of
which are dependent on LT R signaling (70, 74, 75) . TLS formation in tumors is associated with better patient
outcomes, and when LIGHT is delivered to tumors, stromal LT R activation induces TLSs formation (57, 59).
Such ectopic TLS formation increases lymphocyte and DC trafficking to increase tumor antigen surveillance and
subsequent lymphocyte activation. Johansson-Percival et al. demonstrated the benefits of LIGHT induced TLS
formation in vivo in a pancreatic insulinoma model (59). TLS mediated tumor destruction however, cannot take
place without its recruited cells. LIGHT induced TLSs allow for tumor combat in a myriad of ways.
Tumor Destruction & Amplified Tumor Specificity
LIGHT associated HEVs, TLSs, and T cell costimulation enable the immune system to combat the tumor.
Due to the incomplete lymphatic structure of induced TLSs, HEVs are able to recruit naïve CD4
+
T cells, CD8
+
T cells, DCs, macrophages, and NKs into TLSs to recognize tumor associated antigens. CCR7
+
DCs are recruited
to TLSs via stromal CCL21 expression, and subsequent tumor antigen presentation in TLSs increases the
probability of tumor immunity via T cell priming (32, 75). Such T cell priming was shown to happen in a
intratumoral manner as described by Yu et al. (76). Normalizing tumor vasculature allows for increased
circulating lymphocytes, and HEV formation allows for the further construction of TLSs to allow lymphocyte
17
priming and activation via DC and NK cells. LIGHT has also been found to induce DC maturity within a CT26
colon carcinoma model (77). Fan et al. also found NK driven CD8+ T cell priming via HVEM to be just as
essential to tumor regression as well (55). Once activated, CD8+ effector T cells function as the primary agent to
mediate tumor regression (77). LIGHT expressed within Ag104L
D
tumors found LIGHT-dependent increases in
intratumoral IFN and TNF , which were correlated to increased tumor infiltrating lymphocytes compared to
controls (31, 55). Kanodia et al. noted increased amounts of inflammatory cytokines MIG and IP-10 to support
the notion that T cells are undergoing a Th1 type response (62). Removing CD8+ T cells in multiple models ablate
therapeutic responses of LIGHT delivery (31, 76). Furthermore, LIGHT-treated cancers were found to reject
tumor rechallenge at distal sites, highlighting the existence of memory responses (31, 62, 77). By utilizing the
diverse functions of LIGHT, researchers have been able to elicit IFN -mediated apoptosis, tumor vasculature
normalization, HEV formation TLS formation, and CD8
+
T cell mediated tumor eradication.
IV. LIGHT Delivery Systems
In the presence of an established suppressive TME, the generation of tumor-specific effector responses,
infiltration of such effector cells into tumors, and creation of anti-tumor memory have been difficult obstacles to
overcome with regards to cancer immunotherapy (78). Multiple cancer models have been shown to have naturally-
occurring tumor-specific lymphocytes (8). However, the ability of these effector lymphocytes to penetrate is
typically poor, and successful infiltration into the tumor dictates prognostic outcomes (15, 16). Effective delivery
of LIGHT to tumor sites not only overcomes each of these problems through effector cell infiltration, vascular
normalization, HEV formation, TLS formation, and T cell mediated tumor destruction, but also tips the scales in
favor of tumor clearance by the immune system that also leads to the generation of anti-tumor memory. Over the
past two decades, researchers have investigated the use of gene transfer, adoptive transfer, viral vectors, and
peptides as delivery systems for LIGHT to facilitate this process.
18
Gene Transfer of LIGHT Expressing Tumors
Researchers first assessed LIGHT’s in vivo abilities to reduce cancer burden via direct transfection of
tumor cells and adoptively transferring them into mice. Ag104L
D
is an aggressive fibrosarcoma that is unaffected
by most immunotherapies, and remains to be a popular model line for LIGHT (16). Papers by Yu et al. and Fan
et al. demonstrate LIGHT, when expressed on Ag104L
D
tumors in an immunocompetent setting get rejected and
are unable to reestablish themselves (31, 55, 76). Intratumoral lymphocyte tumor priming was deduced by Yu et
al. with the use of 2C and P14 T cells. 2C T cells lack the ability to indirectly activate (thus requiring direct tumor
binding), and the P14 T cells were engineered to be nonresponsive to Ag104L
D
(31). In a primary Ag104L
D
or
Ag104L
D
LIGHT
+
tumor challenge followed by a distal Ag104L
D
challenge, Yu et al. found up to 100x more
intratumoral 2C T cells than P14 T cells in distal metastasis sites of Ag104L
D
LIGHT
+
mice than the control (31).
Such an increase of 2C T cells in distal tumor sites demonstrate direct Ag104L
D
tumor priming via LIGHT
costimulation.
Researchers discovered further insights of LIGHT gene transfer in different models. Fan et al. established
the vital role of LIGHT-HVEM in the Ag104L
D
LIGHT
+
model on NK cells activating CD8
+
cells before tumor
priming (55). Furthermore, Zhai et al. forced LIGHT expression in MDA-MB-231 human breast carcinoma cells
via retrovirus and found significant inhibition of tumor growth upon challenge compared to controls (79). Qiao
et al. transfected CT26 colorectal cancer models to express LIGHT constitutively, and were able to stunt tumor
growth, lower distal liver metastasis burden, and reject tumor rechallenge (77). Further investigation showed a
marked increase in tumor infiltrating lymphocytes, increased IFN levels, and higher concentration of the DC
activation marker CD86 compared to control (77). With the literature establishing that LIGHT-expressing tumors
mediate decreased tumor burden, Adenovirus based methods of LIGHT expression have been explored as well to
assist LIGHT delivery into tumors.
19
Adenovirus Vectors
Scientists have reliably used adenovirus to force tumors into expressing antigens of different varieties,
however positive outcomes require further immunostimulation due to the immunosuppressive TME (80, 81).
Adenoviruses carrying LIGHT have been shown to provide the extra push needed. Advantages of Adenovirus
delivery systems include their immunogenicity to act as an adjuvant, their lack of replication, their promiscuity
in cell binding, as well as their ability to force cellular expression of target proteins (32). Following in vitro
success of adenoviruses carrying LIGHT (Ad-LIGHT) to inhibit tumor growth, researchers have been able to
elicit robust anti-tumor responses as well as distal metastasis rejection in vivo (66). In 2007, Yu et al. was able to
reject established tumors as well as distal metastases with intratumoral adenovirus injection carrying LIGHT (Ad-
LIGHT) (31). Such models include aggressive fibrosarcoma Ag104L
D
and mammary carcinoma 4T1. Within the
tumors, the researchers indicated increased tumor specific CD8
+
T cell infiltration and cytokine expressions of
IFN and TNF compared to Adenovirus control and no treatment. With such success however, researchers must
be careful to account for the drawbacks of Adenovirus based therapy.
Adenovirus treatments have a couple disadvantages as well. Often, Adenovirus based treatments require
intratumoral injection, which can make treating inaccessible tumors difficult (80). Furthermore, the immune
system can mount a response against the Adenovirus itself and not the tumor (81). In case of such Adenoviral
immunity, multiple serotype options of Adenovirus must be available as a therapeutic vehicle as well. Regardless,
Yu et al. gene transfer therapy and Adenovirus therapy delivering LIGHT to the TME set the precedent of research
to come over the following decade. Several studies have found success delivering LIGHT via adoptive transfer
of LIGHT expressing cells as well as fusion peptides.
Adoptive Transfer of LIGHT Expressing Cells
Novel adoptive transfer methods are always being considered in the advancement of tumor targeting. An
interesting method of delivery includes the tumor targeting properties of bacteria. Salmonella has been shown to
localize and grow within tumors: most likely due to the immunosuppressive nature of the tumor
20
microenvironment shielding the bacteria from the immune system or the tumors’ hypoxic areas can nurture the
growth of facultative anaerobes (82, 83). Loeffler et al. designed an attenuated (endotoxin free) Salmonella
typhirium to deliver LIGHT to specifically localize to tumors (82). In vivo results in D2F2 breast and CT-26 colon
carcinoma models revealed significant reduction in growth for both lines, more so in the CT-26 model. Along
with bacteria, bone marrow derived mesenchymal stem cells (MSC) have been utilized in LIGHT based therapies
to target tumors through a sort of Trojan Horse method.
A recent tumor targeting method takes advantage of cancer endothelial cells’ ability of attracting MSCs
(84, 85). Instead of utilizing bacteria or lymphocytes, Zou et al. developed a technique for the adoptive transfer
of MSC expressing LIGHT (86). By infecting MSC with retrovirus to express LIGHT, Zou et al. utilized MSC-
LIGHT in either a prophylactic (injection of MSC-LIGHT 13 days before challenge) or therapeutic manner
(injection of MSC-LIGHT 7 days after challenge) against the TUBO mammary cancer model (86). Profound
increases in intratumoral CD4
+
and CD8
+
T cells were found in both treatment groups as they repressed tumor
growth compared to the controls. However, no tumor rejection was recorded; most likely due to complex MSC
properties that promote tumor growth (84). Interestingly, removing CD4
+
T cells ablated MSC-LIGHT’s
prophylactic efficacy while removing CD8
+
T cells removed MSC-LIGHT’s therapeutic efficacy. CD4
+
T cells
were perhaps utilized more in the prophylactic scenario due to MSC’s ability to act as antigen presenters to prime
CD4
+
cells (86). Memory was retained in TUBO rechallenge, and anti-LT R Ig removed MSC-LIGHT’s efficacy
as well. Along with the adoptive transfer of LIGHT expressing cells, researchers have been assessing the viability
of targeting peptides to deploy LIGHT.
Antibody Fusion Proteins
Rather than using tumor homing cells or virus, LIGHT bound tumor targeting antibodies have found
success in homing tumors. Tang et al. found success in combining three units of hmLIGHT (discussed further in
section VI) with a functional chain (Fc) of immunoglobulin G (IgG) recognizing Epidermal Growth Factor
Receptor (EGFR) (16). The product (anti-EGFR-hmLIGHT) was used to treat Ag104L
D
fibrosarcoma and MC38
21
colon adenocarcinoma models (16). Anti-EGF-hmLIGHT treatment induced complete tumor regression of
Ag104L
D
-EGFR
+
primary tumors as well as distal rechallenge (16). Anti-EGFR-hmLIGHT induced significant
reduction of growth in CD38 models as well. Tang et al. established this treatment was T cell dependent based
on the 300% - 500% increase of intratumoral CD8
+
T cells as well as increased IFN and TNF . LT R was found
to be the principle receptor for this therapy due to the increase in CCL21 and complete hindrance of anti-tumor
effect of anti-LT R Ig treatment alongside anti-EGFR-hmLIGHT. Section V will further clarify the work of Tang
et al. in relation to the therapeutic efficacy of anti-EGFR-hmLIGHT in conjunction with checkpoint inhibitor
anti-PD-L1. Further LIGHT derived peptide deliveries include tumor vasculature targeting by Johansson-Percival
et al.
Vascular Targeting Peptides
Perhaps the most engrossing LIGHT delivery method lies in peptide delivery, specifically to tumor
angiogenic vessels. Constitutive tumor expression of LIGHT has demonstrated effectiveness, however adoptive
transfer of tumor cells is not the most direct approach of targeting LIGHT to tumors. Because tumor angiogenic
vessels are fundamentally different from healthy vasculature, researchers sought to target them to eliminate the
need for invasive delivery strategies such as intratumoral injection (68).
Table 1: Vascular Targeting Peptides in Relation to LIGHT Therapy
Vascular Targeting Peptide
Amino Acid Sequence
Targeted Moiety LIGHT - Model Lines
CGKRK Hypothesized to target tumor
vasculature specific heparan
sulfates, phosphatidylserine or
VEGF related matrices
Murine glioblastoma
Murine pancreatic insulinoma
Human astrocytoma
Human grade I meningioma
CRGRRST (RGR) PDGFR Murine breast cancer
Murine pancreatic insulinoma
Murine glioblastoma
Human astrocytoma
Human grade I meningioma
CNGRCG (NGR) Tumor specific Aminopeptidase
N/CD13
Human astrocytoma
Human grade I meningioma
22
Researchers used phage libraries to discover short peptide sequences that specifically target tumor
angiogenic vasculature and fused them onto the C-terminus of LIGHT (87, 88). By trafficking LIGHT to tumors
with covalently attached vascular targeting peptides (LIGHT-VTP), scientists have found success in specifically
targeting tumor vasculature, normalizing tumor angiogenic vessels, creating HEVs, creating TLSs, combatting
burden, and inducing memory to reject tumor rechallenge.
Of the several VTPs screened via phage display, three have taken the spotlight in conjunction with LIGHT.
Each VTP contains distinct tumor specific targets. Amino acid sequence CGKRK has been shown to specifically
bind tumor blood vessels, supposedly via either heparan sulfates, phosphatidylserine, or VEGF related matrices
(23, 87). Cancer models demonstrating the utility of LIGHT-CGKRK include murine glioblastoma, murine
pancreatic insulinoma, human astrocytoma and human grade I meningioma (17, 59, 89). Amino acid sequence
CRGRRST (abbreviated RGR) binds specifically to platelet-derived growth factor receptor (PDGFR ), and has
shown success in delivering LIGHT to tumor vasculature in murine pancreatic insulinoma, murine breast cancer,
as well as human glioblastoma samples (17, 58, 59, 88, 90). Amino acid sequence CNGRCG (NGR): the only
VTP used in clinical trials today, binds tumor specific aminopeptidase N/CD13 (17, 91). N/CD13 has been shown
to be important in tumor angiogenesis, and during clinical trials NGR has delivered TNF to refractory solid
tumors and ovarian cancer (23, 92-97). LIGHT-NGR sequences have been able to bind human astrocytoma and
human grade I meningioma (17). Although LIGHT-VTP outcomes are promising, the most effective LIGHT
treatments rely on combinations of either therapeutic vaccinations or checkpoint inhibitors.
V. LIGHT Combination Therapies
LIGHT + Therapeutic Vaccinations
Tumor vaccines are therapeutic vaccines that are given with the intent to stimulate an immune response
directed against identified or neo-antigens occurring within tumors (98). Although tumor vaccines alone do not
generate reliable survival outcomes, combining them with LIGHT treatment further assists naïve T cells in
23
recognizing tumors (72). Multiple groups have demonstrated the benefits of combining therapeutic vaccines with
LIGHT based therapies (59, 62, 99).
Researchers were able to significantly reduce tumor growth in TRAMP-C2 prostate cancer tumors with a
joint treatment of Ad-LIGHT followed by prostate tumor associated antigen tumor vaccine (PSCA trivax)
compared to Ad-LIGHT treatment alone (99). Similar results were found in a murine pancreatic insulinoma model
utilizing LIGHT-VTP therapy (59). In association with increased intratumoral CD8
+
T cells, Yan et al. found
Ad-LIGHT + PSCA trivax combination therapy prevented the maturation of intratumoral Tregs as well (99).
Along with utilizing tumor associated antigens in a therapeutic vaccine, Kanodia et al. have illustrated the efficacy
of Ad-LIGHT therapy in conjunction with anti-tumoral vaccines against viral driven cancers.
Kanodia et al. studied the effects of Ad-LIGHT therapies against human papillomavirus (HPV) 16
transformed cancer (62). HPV16 driven cancers are advantageous models due to the expression of foreign viral
antigens that accompany the tumor (62, 100). Within the HPV 16 C3.43 HPV16 transformed tumor line, the
treatment by Ad-LIGHT and HPV16-E7 expressing Venezuelan equine encephalitis virus replicon particles
(VRP) as a tumor vaccine yielded significant regression of established tumors compared to Ad-LIGHT alone or
HPV-VRP alone (62). This combination treatment lead to increased intratumoral anti-E7 CD8
+
T cells as well as
the presence of intratumoral inflammatory cytokines and activation markers IFN , IL-1a, MIG, and MIP-2.
Furthermore, mice treated with Ad-LIGHT and tumor vaccine were able to generate memory. Upon rechallenge,
75% of the combined Ad-LIGHT and HPV16-E7-VRP combination group survived and 62% of the combined
treatment group were tumor free. Alongside the use of tumor vaccines, checkpoint inhibitors are becoming a more
common addition to the LIGHT therapy arsenal.
LIGHT + Checkpoint Inhibitors
Because IFN is a main effector of LIGHT based treatment, and tumor PD-L1 is upregulated in the
presence of chronic exposure to IFN , scientists found synergy with the combination treatment of LIGHT and
anti-PD-L1 antibodies (21, 101). Tang et al. found the combination treatment of anti-PD-L1 antibodies with anti-
24
EGFR-hmLIGHT conferred the best treatment outcomes within their cancer models (16). As tumor size grew,
LIGHT based therapy lost efficacy due to the tumor’s increased PD-L1 concentration from effector T cell IFN .
In conjunction, anti-PD-L1 efficacy was raised due to increased CD8
+
T cell concentrations within the tumor.
Inhibiting PD-L1 allowed for further infiltration of T cells via anti-EGFR-hmLIGHT within the Ag104L
D
and
MC38 tumor models, allowing for complete rejection of tumors whereas single treatments of either were
ineffective. This synergy contributes to the evidence highlighting the efficiency of a checkpoint inhibitor depends
on the ability of T cells to infiltrate a tumor (15, 16). Johansson-Percival et al. furthered checkpoint inhibitor
combination therapy by utilizing anti-CTLA-4 as well.
Johansson et al. have demonstrated within the murine pancreatic insulinoma model that the combination
of LIGHT-VTP with anti-PD-1 and anti-CTLA-4 checkpoint inhibitors (dual checkpoint therapy) have been the
most effective in combatting the tumor microenvironment (59). By utilizing LIGHT-VTP and dual checkpoint
therapy, Johansson-Percival et al. were able to confer a 6-week survival advantage along with vascular
normalization and production of TLSs containing HEVs (59). Furthermore, including an anti-Tag-CpG-ODN
tumor vaccine within Tag
+
tumors to the triple treatment regimen elicited a 13-week survival improvement
compared to LIGHT-VTP and dual checkpoint therapy (59). This was the first time LIGHT-VTP was utilized
with both checkpoint inhibitors as well as a tumor vaccine. Given the multiple promising outcomes from this
work, further study of checkpoint inhibitor and tumor vaccine combination therapies is necessary for the future
of LIGHT cancer research.
VI. Future Directions
Due to the variety of LIGHT’s downstream effects, delivery methods, and treatment combinations, it
comes to no surprise that further research must be conducted to optimize treatment outcomes. Ongoing LIGHT
research will have to investigate tumor normalization metrics, recognize vascular mimicry, account for DcR3,
probe for novel immunotherapy combinations, explore various LIGHT fusion protein conformations, and mitigate
the lack of cross species LIGHT functionality to maximize LIGHT’s therapeutic potential.
25
When assessing tumor vascular normalization, there are many more parameters to account for than
pericyte contractile markers. Carmeliet & Jain stress the use of the vascular normalization index, which accounts
for changes in vascular flow, permeability, microvascular volume, and the basement membrane remodeling
parameters of systemic collagen IV (69). Such vascular normalization parameters should be taken into account
for the multiple varieties of LIGHT-VTP. Furthermore, within glioblastoma tumor models, He et al. must be
aware of the effects of vascular mimicry.
Vascular mimicry marks the event of tumor cells transforming into functional endothelial cells, and has
been demonstrated to occur within glioblastoma models (85, 102). Since the LIGHT-VTP treatments from He. et
al. are tested on glioblastoma models as well, the pathogenic potential of vascular mimicry form cancer stem cells
must still be accounted for (17). Although LIGHT-VTPs can bind and induce vasculature normalization, the lack
of DcR3 should be accounted for in murine tumor models.
Future research should account for DcR3, the soluble inhibitor of LIGHT. DcR3 is not expressed in murine
models, and physiological concentrations are undetectable in humans (44, 48). Since DcR3 has been implicated
in lung, colon, and liver cancer models, inhibitors of DcR3 should be investigated or considered if LIGHT based
therapies fail in human trials (49, 50). Along the same line of thinking, inhibiting a LIGHT inhibitor can be of
use when considering immunotherapeutic combinations.
The use of LIGHT in conjunction with checkpoint inhibitors and tumor vaccines have proven successful,
however there may be even further immunotherapeutic combinations to explore (59, 62). BTLA is an inhibitor
for LIGHT, and has been shown to down regulate T cell mediated responses (103). Immune adjuvant CpG is able
to activate toll-like receptor 9 (TLR9), and was successfully utilized to downregulate BTLA and enhance CD8
+
maturity within the melanoma Melan-A
MART-1
tumor model (59, 103). This vaccine adjuvant also found success
in the LIGHT-VTP combination therapies used by Johansson-Percival et al. in pancreatic insulinomas (59).
Understanding CpG to downregulate a known LIGHT inhibitor may prove useful. It must be noted that other,
possibly more effective isoforms of LIGHT can yet be designed.
Other isoforms of LIGHT-VTP can be considered to assess therapeutic improvements. It has been shown
that LIGHT has a N terminal cytosolic portion and C terminal extracellular portion (33, 44, 79). Rather than
26
placing vascular targeting moieties on the C terminal end of LIGHT, researchers have yet to place it on the N
terminus to better mimic the natural structure of LIGHT: facing the lumen. This could prove challenging however,
because recombinant murine LIGHT is difficult to make on account of instability and insolubility (16, 104).
Further, it is critical to highlight that murine LIGHT and human LIGHT are not interchangeable.
Although the functions of murine and human LIGHT are identical, human LIGHT does not bind to murine
LIGHT receptors (16). Tang et al. designed a bi-species binding LIGHT that was able to bind both human and
murine ligands called hmLIGHT to elicit anti-tumoral activity (16). When moving forward with LIGHT based
treatments, researchers must account for the lack of cross-species specificity when using LIGHT, and perhaps
utilize recombinant hmLIGHT moving forward.
VII. Conclusion
Despite improvements in immunotherapy, eliciting immunogenic responses against tumors remain a
current challenge. LIGHT based therapies have shown great effectiveness in reducing tumor burden and
generating lasting immunogenic memory by initiating inflammatory responses, tertiary lymphoid structure
neogenesis, and tumor vascular normalization. Furthermore, by markedly increasing the expression of
inflammatory cytokines, LIGHT initiates tumor specific T cell activation, maturation, and penetration. LIGHT-
LT R dependent pathways initiate vascular normalization to further ameliorate tumor angiogenic burden and
increase lymphocytic function. Intratumoral delivery of LIGHT is the vital step in ameliorating tumor burden as
Adenovirus vectors, adoptive transfer, antibodies, and vascular targeting peptides are being investigated
worldwide. LIGHT mediated anti-tumor effects have been shown to compound with combination treatments such
as IFN , tumor vaccines, and checkpoint inhibitors. Future directions of LIGHT therapeutics will have to consider
further metrics of tumor vascular normalization, vascular mimicry, DcR3, immunotherapy combinations, and
viable LIGHT isoforms. The insights of LIGHT research provided in the recent decades warrant continued
investigation of its use as a cancer therapeutic.
27
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Abstract (if available)
Abstract
The continuing need for novel cancer therapies has turned its gaze towards the tumor necrosis factor superfamily member 14 (TNFSF 14), also known as LIGHT. LIGHT (homologous to lymphotoxins, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T cells) is a pro-inflammatory costimulatory protein expressed on immature dendritic cells, activated natural killer cells, and activated T cells. By eliciting robust anti-tumor responses via interferon γ mediated apoptosis, tumor angiogenic vascular normalization, high endothelial venule formation, tertiary lymphoid structure formation, and immune activation, LIGHT has piqued the interest of researchers over the past two decades. By delivering LIGHT properly to tumors via gene transfer, Adenovirus vectors, adoptive transfer, antibodies, or vascular targeting peptides, LIGHT has shown promise as a new candidate in cancer immunotherapy. This review will further clarify the diverse effects, deliveries, and immunotherapeutic combinations LIGHT has to offer.
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Otsmaa, Mikk
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Core Title
Let there be LIGHT: TNFSF14 immunomodulating properties for cancer immunotherapy
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Keck School of Medicine
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Master of Science
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Molecular Microbiology and Immunology
Publication Date
07/15/2019
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06/14/2019
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cancer,Combination Therapy,immunotherapy,Light,OAI-PMH Harvest,TNFSF14,tumor necrosis factor family,vascular normalization,vascular targeting peptide
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immunotherapy
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tumor necrosis factor family
vascular normalization
vascular targeting peptide