Additional Effector T-cell Pathways
- PD-1 Pathway
- CTLA-4 Pathway
- Additional Effector T-Cell
- SLAMF7 Pathway
- Additional NK Cell
- Non-effector Cell
LAG-3: impairs T-cell function and can mark exhausted T cells
Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor expressed on the surface of both activated cytotoxic T cells and regulatory T cells (Tregs).1,2 The antigen-presenting complex, major histocompatibility complex (MHC), presents antigen for recognition by T cells and is one of the ligands for LAG-3.2,3 LAG-3 can negatively regulate T-cell proliferation and the development of lasting memory T cells.4Similar to the expression and function of PD-1, repeated exposure to tumor antigen causes a continual increase in the presence and activity of LAG-3. This unrelenting signaling leads to T-cell exhaustion.5,6 Exhausted T cells have an impaired ability to fight tumor cells, which may result in tumor growth.6 T cells co-expressing both LAG-3 and PD-1 may show an even greater degree of exhaustion compared with those expressing LAG-3 alone.7
LAG-3 can also trigger the immunosuppressive activity of Tregs.1 In cancer, Tregs expressing LAG-3 gather at tumor sites and show potent suppression of cytotoxic T cells.8
Increased LAG-3 expression has been associated with poorer prognosis in multiple tumor types.9,10
In preclinical studies, when the PD-1 pathway is blocked, LAG-3 may be upregulated to maintain tumor growth.11 Research is ongoing to understand how dual inhibition of LAG-3 and other checkpoint pathways may synergistically increase T-cell antitumor activity compared with inhibition of either pathway alone.
CD137: potentiator of innate and adaptive immunity
CD137, or 4-1BB, is an activating receptor. Because it appears on both natural killer (NK) cells and T cells, CD137 can trigger both innate and adaptive immunity.1,2 After these cells have been activated by exposure to tumor antigen, CD137 signals stimulate them to reproduce and to generate antitumor activity.1,2 In animal models, CD137 also plays a critical role on T cells in the development of immune memory and the creation of a durable immune response.3
On lymphocytes, the presence of CD137 appears to be a marker for tumor reactivity—the ability to react to tumor antigen and mount an immune response.4
Based on preclinical data, activation of CD137 signaling can stimulate both cytotoxic T-cell and NK-cell activity, and generate a lasting memory response.5,6
GITR: energizes the T-cell response to antigen
Glucocorticoid-induced TNFR-related protein (GITR) is an activating receptor on the surface of T cells and other immune cells.1,2
Cytotoxic T cells can recognize and attack tumor cells.3 Once exposure to tumor antigen activates a T cell, the number of GITR receptors on its surface increases.1,4 On the activated T cell, GITR acts as a costimulatory receptor, meaning that it is a receptor whose signaling enhances cell reproduction and the generation of cancer-killing activity.5
Exposure to tumor antigen also activates GITR on regulatory T cells (Tregs). Tregs act to limit the immune response.6 GITR signaling can block the suppressive abilities of Tregs, further enhancing cytotoxic T-cell function.6
In preclinical studies, activation of GITR signaling can help enhance immunity through the activation of cytotoxic T cells and inhibition of Treg activity.7
ICOS: co-stimulates T-cell activation and proliferation
Inducible T-cell co-stimulator (ICOS) is an activating receptor expressed on the surface of activated cytotoxic T cells, regulatory T cells (Tregs), NK cells, and other types of T cells.1-5 While similar in structure to the receptor cytotoxic T-lymphocyte antigen 4 (CTLA-4), ICOS has a distinct and opposing function.2,6 The ligand for ICOS—ICOSL (B7RP-1)—is expressed on antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages.6,7
ICOS/ICOSL signaling leads to the activation, proliferation, and survival of cytotoxic T cells, as well as the survival of memory T cells.8-10 Following T-cell activation, upregulation of ICOS perpetuates T-cell proliferation and function.9,11 It has been suggested that ICOS/ICOSL signaling may enhance activated NK-cell function.5
In preclinical studies, ICOS signaling was necessary for the activation, proliferation, and function of cytotoxic T cells under native conditions as well as during the blockade of CTLA-4.12,13 This stimulation of ICOS during CTLA-4 blockade was shown to enhance T-cell activity.12 In addition, mouse models demonstrate that ICOS expression may enhance the antitumor response of NK cells.5
OX40: activates and amplifies T-cell stimulation
OX40 is an activating receptor expressed on the surface of activated cytotoxic T cells and regulatory T cells (Tregs).1-3 OX40 plays a dual role in the immune response, both activating and amplifying T-cell responses.
Activation: cytotoxic T cells are able to recognize and attack tumor cells. On cytotoxic T cells, OX40 binds to its ligand (OX40L), resulting in stimulatory signals that promote T-cell reproduction, function, and survival.4-6
Amplification: Tregs act to limit the immune response. OX40/OX40L signaling blocks the ability of Tregs to suppress T cells and reduces Treg generation.7 By inhibiting the immunosuppressive effect of Tregs and limiting their population, OX40 further amplifies the impact of T-cell activation.
The dual effects of OX40 help create a tumor microenvironment that is more favorable to the antitumor immune response. Cytotoxic T cells are increased in number and activity and the immunosuppressive impact of Tregs is curtailed. These shifts have been demonstrated in preclinical studies of OX40 signaling.8-10
TIGIT: overpowers cytotoxic T-cell function and proliferation
T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is an immune checkpoint receptor expressed on the surface of cytotoxic, memory, and regulatory T cells (Tregs), as well as natural killer (NK) cells.1,2 TIGIT has 2 ligands: CD155 (PVR) and CD112 (Nectin2).1,2 On cytotoxic T cells and NK cells, interaction of TIGIT with either of its ligands suppresses immune activation.1,2 When TIGIT is expressed on Tregs, however, this interaction enhances their ability to suppress the immune response.3
In the normal immune system, the suppressive effect of TIGIT is counterbalanced by the immune-activating receptor CD226 (also called DNAM1). Also expressed on cytotoxic T cells and NK cells, DNAM1 competes with TIGIT to bind to CD155 and CD112.4,5 The inhibitory signal provided by TIGIT overpowers the ability of DNAM1 to stimulate T-cell activation.5
Tumor cells exploit the dominance of the inhibitory TIGIT pathway to avoid immune-mediated destruction. In cancer, increased presence of TIGIT and its ligands is associated with impaired DNAM1 signaling and a progressive loss of T-cell function through a process known as T-cell exhaustion.6-8
Based on preclinical studies, inhibition of TIGIT signaling increases the proliferation and function of cytotoxic T cells.7,9
TIM-3: exhausts both innate and adaptive effector cells
T-cell immunoglobulin and mucin-3 (TIM-3) is an immune checkpoint receptor involved in the suppression of both innate and adaptive immune cells.1 It is expressed on a wide variety of immune cells, including cytotoxic T cells, regulatory T cells (Tregs), natural killer (NK) cells, and antigen-presenting cells (APCs) such as dendritic cells (DCs).1,2 TIM-3 can suppress effector cells through the interaction with a broad array of ligands: carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), galectin-9, phosphatidylserine (PS), and high mobility group box 1 (HMGB1).1,3
TIM-3 has multiple suppressive effects on effector T cells.4 Increased T-cell expression of TIM-3 as well as its co-expression with CEACAM1 correlate with T-cell exhaustion.5,6 TIM-3 can also indirectly suppress effector T-cell activity by acting on myeloid-derived suppressor cells (MDSCs), Tregs, and DCs.7-9
- Binding of TIM-3 on cytotoxic T cells to galectin-9 on immunosuppressive MDSCs can enhance MDSC expansion and suppressor activity.7
- Expression of TIM-3 on Tregs can reduce T-cell function and proliferation.9
- The interaction of PS or HMGB1 with TIM-3 on tumor-infiltrating DCs may impair DC ability to activate T-cells and promote inflammation.4,8,10
Increasing expression of TIM-3 on NK cells has also been associated with NK-cell exhaustion.1 In addition, the interaction of TIM-3 on NK cells with galectin-9 or PS can promote their dysfunction.11,12
The expression of TIM-3 is upregulated on NK cells, T cells, and Tregs in various cancers.11,13
Preclinical data suggest that the blockade of TIM-3 can rescue NK-cell activity, promote tumor antigen processing, and reinvigorate exhausted T cells, restoring their proliferation and function.4,5,11,14 TIM-3 is often co-expressed with other immune checkpoint receptors, and preclinical studies indicate that co-blockade of TIM-3 with another immune checkpoint receptor may further reinvigorate exhausted T cells.5,15,16
Oncolytic viruses: attack tumor cells to stimulate T-cell activity
Oncolytic viruses are naturally or genetically engineered viruses that preferentially target and replicate within tumor cells, leading to tumor cell destruction.1-3 Tumor cells often have altered molecular mechanisms favoring viral replication, which may make them uniquely susceptible to viral infection and propagation.3 Similar to immune signaling pathways, viral infection can influence the antitumor immune response.4
To initiate infection, oncolytic viruses recognize and attach to receptors that are highly expressed on tumor cells.2 Once internalized, they replicate and produce viral proteins.2,5 This process ultimately causes host tumor cell lysis, or death, releasing tumor antigens and new viruses into the tumor microenvironment.1,5
Oncolytic viruses can be either “unarmed” or “armed.” Both types of virus can activate an antitumor immune response, in part by promoting tumor inflammation:
- Unarmed oncolytic viruses lyse host cells, which can lead to the release of tumor antigens that prime and activate cytotoxic T cells to infiltrate and kill the tumor2,5
- Research is ongoing to determine how armed oncolytic viruses are engineered to initiate tumor-cell expression of immunomodulatory proteins, in addition to lysing host cells. These proteins can further activate the antitumor immune response5-8
Preclinical models demonstrate that unarmed oncolytic viruses can cause the release of tumor antigens, promoting the activation of cytotoxic T cells.9 In addition, immunomodulatory proteins expressed by armed viruses may stimulate tumor inflammation and further enhance cytotoxic T-cell activation as shown in preclinical studies.10-12
Research to further understand these pathways is ongoing.
REFERENCES – LAG-3
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- Baixeras E, Huard B, Miossec C, et al. Characterization of the lymphocyte activation gene 3–encoded protein: a new ligand for human leukocyte antigen class II antigens. J Exp Med. 1992;176(2):327-337.
- Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol. 1995;25(9):2718-2721.
- Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali AA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172(9):5450-5455.
- Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29-37.
- Goding SR, Wilson KA, Xie Y, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-4909.
- Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107(17):7875-7880.
- Camisaschi C, Casati C, Rini F, et al. Cutting-edge: LAG-3 expression defines a subset of CD4+ CD25high Foxp3+ regulatory T cells that are expanded at tumor sites. J Immunol. 2010;184(11):6545-6551.
- Deng W-W, Mao L, Yu G-T, et al. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5(11):e1239005.
- Yang Z-Z, Kim HJ, Villasboas JC, et al. Expression of LAG-3 defines exhaustion of intratumoral PD-1+ T cells and correlates with poor outcome in follicular lymphoma. Oncotarget. 2017;8(37):61425-61439.
- Huang R-Y, Francois A, McGray AJR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2017;6(1):e1249561.
REFERENCES – CD137
- Pollok KE, Kim YJ, Zhou Z, et al. Inducible T cell antigen 4-1BB: analysis of expression and function. J Immunol. 1993;150(3):771-781.
- Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L. NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol. 1998;190(2):167-172.
- Willoughby JE, Kerr JP, Rogel A, et al. Differential impact of CD27 and 4-1BB costimulation on effector and memory CD8 T cell generation following peptide immunization. J Immunol. 2014;193(1):244-251.
- Ye Q, Song DG, Poussin M, et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res. 2014;20(1):44-55.
- Melero I, Shuford WW, Newby SA, et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med. 1997;3(6):682-685.
- Murillo O, Arina A, Hervas-Stubbs S, et al. Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res. 2008;14(21):6895-6906.
REFERENCES – GITR
- Gurney AL, Marsters SA, Huang A, et al. Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr Biol. 1999;9(4):215-218.
- Hanabuchi S, Watanabe N, Wang YH, et al. Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL) Blood. 2006;107(9):3617-3623.
- Martínez-lostao L, Anel A, Pardo J. How do cytotoxic lymphocytes kill cancer cells? Clin Cancer Res. 2015;21(22):5047-5056.
- Kanamaru F, Youngnak P, Hashiguchi M, et al. Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol. 2004;172(12):7306-7314.
- Tone M, Tone Y, Adams E, et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A. 2003;100(25):15059-15064.
- Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002;3(2):135-142.
- Cohen AD, Schaer DA, Liu C, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010. doi:10.1371/journal.pone.0010436.
REFERENCES – ICOS
- Harada H, Salama AD, Sho M, et al. The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. J Clin Invest. 2003;112(2):234-243.
- Zheng J, Chan P-L, Liu Y, et al. ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner. PLoS One. 2013;8(12):e82203.
- Tu J-F, Ding Y-H, Ying X-H, et al. Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival. Sci Rep. 2016;6:35056.
- Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-548.
- Ogasawara K, Yoshinaga SK, Lanier LL. Inducible costimulator costimulates cytotoxic activity and IFN-γ production in activated murine NK cells. J Immunol. 2002;169(7):3676-3685.
- Rudd CE, Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol. 2003;3(7):544-556.
- Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1-S8.
- Burmeister Y, Lischke T, Dahler AC, et al. ICOS controls the pool size of effector-memory and regulatory T cells. J Immunol. 2008;180(2):774-782.
- Hutloff A, Dittrich AM, Beier KC, et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature. 1999;397(6716):263-266.
- Yoshinaga SK, Whoriskey JS, Khare SD, et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature. 1999;402(6763):827-832.
- Dong C, Juedes AE, Temann U-A, et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature. 2001;409(6816):97-101.
- Fan X, Quezada SA, Sepulveda MA, Sharma P, Allison JP. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med. 2014;211(4):715-725.
- Fu T, He Q, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti–CTLA-4 therapy. Cancer Res. 2011;71(16):5445-5454.
REFERENCES – OX40
- Evans DE, Prell RA, Thalhofer CJ, Hurwitz AA, Weinberg AD. Engagement of OX40 enhances antigen-specific CD4+ T cell mobilization/memory development and humoral immunity: comparison of αOX-40 with αCTLA-4. J Immunol. 2001;167(12):6804-6811.
- Ruby CE, Redmond WL, Haley D, Weinberg AD. Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur J Immunol. 2007;37(1):157-166.
- Tittle TV, Weinberg AD, Steinkeler CN, Maziarz RT. Expression of the T-cell activation antigen, OX-40, identifies alloreactive T cells in acute graft-versus-host disease. Blood. 1997;89(12):4652-4658.
- Godfrey WR, Fagnoni FF, Harara MA, Buck D, Engleman EG. Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor. J Exp Med. 1994;180(2):757-762.
- Bansal-Pakala P, Halteman BS, Cheng MHY, Croft M. Costimulation of CD8 T cell responses by OX40. J Immunol. 2004;172(8):4821-4825.
- Mousavi SF, Soroosh P, Takahashi T, et al. OX40 costimulatory signals potentiate the memory commitment of effector CD8+ T cells. J Immunol. 2008;181(9):5990-6001.
- Vu MD, Xiao X, Gao W, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood. 2007;110(7):2501-2510.
- Piconese S, Valzasina B, Colombo MP. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med. 2008;205(4):825-839.
- Weinberg AD, Rivera MM, Prell R, et al. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol. 2000;164(4):2160-2169.
- Gough MJ, Ruby CE, Redmond WL, Dhungel B, Brown A, Weinberg AD. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res. 2008;68(13):5206-5215.
REFERENCES – TIGIT
- Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10(1):48-57
- Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A. 2009;106(42):17858-17863.
- Joller N, Lozano E, Burkett PR, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40(4):569-581.
- Bottino C, Castriconi R, Pende D, et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med. 2003;198(4):557-567.
- Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 axis regulates human T cell function. J Immunol. 2012;188(8):3869-3875.
- Goding SR, Wilson KA, Xie Y, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-4909.
- Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell. 2014;26(6):923-937.
- Chauvin JM, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. 2015;125(5):2046-2058.
- Joller N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186(3):1338-1342.
REFERENCES – TIM-3
- Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989-1004.
- Han G, Chen G, Shen B, Li Y. Tim-3: an activation marker and activation limiter of innate immune cells. Front Immunol. 2013;4:449.
- Nakayama M, Akiba H, Takeda K, et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009;113(16):3821-3830.
- Chiba S, Baghdadi M, Akiba H, et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012;13(9):832-842.
- Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175-2186.
- Zhang Y, Cai P, Li L, et al. Co-expression of TIM-3 and CEACAM1 promotes T cell exhaustion in colorectal cancer patients. Int Immunopharmacol. 2017;43:210-218.
- Dardalhon V, Anderson AC, Karman J, et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J Immunol. 2010;185(3):1383-1392.
- Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev. 2010;235(1):172-189.
- Gautron A-S, Dominguez-Villar M, de Marcken M, Hafler DA. Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells. Eur J Immunol. 2014;44(9):2703-2711.
- Maurya N, Gujar R, Gupta M, Yadav V, Verma S, Sen P. Immunoregulation of dendritic cells by the receptor T cell Ig and mucin protein-3 via Bruton’s tyrosine kinase and c-Src. J Immunol. 2014;193(7):3417-3425.
- da Silva IP, Gallois A, Jimenez-Baranda S, et al. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res. 2014;2(5):410-422.
- Weber JK, Zhou R. Phosphatidylserine-induced conformational modulation of immune cell exhaustion-associated receptor TIM3. Sci Rep. 2017;7(1):13579. doi:10.1038/s41598-017-14064-x.
- Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014;2(5):393-398.
- Liu J-F, Ma S-R, Mao L, et al. T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer. Mol Oncol. 2017;11(2):235-247.
- Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015;6(1-2):7-17.
- Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187-2194.
REFERENCES – Oncolytic viruses
- Babiker HM, Riaz IB, Husnain M, Borad MJ. Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma. Oncolytic Virother. 2017;6:11-18.
- Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14(9):642-662.
- Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Sci. 2016;107(10):1373-1379.
- Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321-330.
- Seymour LW, Fisher KD. Oncolytic viruses: finally delivering. Br J Cancer. 2016;114(4):357-361.
- Aurelian L. Oncolytic viruses as immunotherapy: progress and remaining challenges. Onco Targets Ther. 2016;9:2627-2637.
- Uusi-Kerttula H, Hulin-Curtis S, Davies J, Parker AL. Oncolytic adenovirus: strategies and insights for vector design and immuno-oncolytic applications. Viruses. 2015;7(11):6009-6042.
- Tysome JR, Lemoine NR, Wang Y. Update on oncolytic viral therapy - targeting angiogenesis. Onco Targets Ther. 2013;6:1031-1040.
- Zamarin D, Holmgaard RB, Subudhi SK, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014;6(226):226ra32.
- Li X, Wang P, Li H, et al. The efficacy of oncolytic adenovirus is mediated by T-cell responses against virus and tumor in Syrian hamster model. Clin Cancer Res. 2017;23(1):239-249.
- Tuve S, Liu Y, Tragoolpua K, et al. In situ adenovirus vaccination engages T effector cells against cancer. Vaccine. 2009;27(31):4225-4239.
- Kim HS, Kim-Schulze S, Kim DW, Kaufman HL. Host lymphodepletion enhances the therapeutic activity of an oncolytic vaccinia virus expressing 4-1BB ligand. Cancer Res. 2009;69(21):8516-8525.