Targeting Both T and NK Cells via TIGIT

Immune checkpoints play a central role in regulating the magnitude and duration of an immune response. When functioning properly, immune checkpoints ensure appropriate response to insults such as infection or malignancy, while also preventing harm to the host from excessive immune reaction. Importantly, dysregulation of immune checkpoints by malignant cells can promote their growth and expansion.1

Given the ability of malignant cells to manipulate immune checkpoints, anti-cancer immunotherapy seeks to reverse these aberrations and instead enhance immune activity against malignant cells.2 Immune checkpoint anti-cancer therapy is an area of active drug development. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied checkpoints to date.3 Unfortunately, the Food and Drug Administration-approved inhibitors that target these immune checkpoints are therapeutically effective in only a fraction of patients with cancer. Furthermore, even when response is achieved, development of resistance to these agents is common.4 As such, there is considerable interest in developing novel immune checkpoint therapies.

T cell immunoglobulin and ITIM domain (TIGIT), also known as WUCAM, Vstm3, and VSIG9, is one such target.5 TIGIT is expressed by both T cells and natural killer (NK) cells.5 Its expression is weak on naïve cells, but is rapidly induced by antigenic challenge or inflammatory stimulus,5 with high expression on tumor infiltrating lymphocytes (TILs).6 TIGIT expression is associated with T cell exhaustion, direct immunosuppression of NK cells, release of the immunoregulatory cytokines, and tumor progression.5,7,8

Preclinical studies have demonstrated dual targeting of TIGIT and PD-1 to produce synergistic immune activation.9 This synergy may be at least partially explained in that in contrast to CTLA-4, PD-1, and PD-L1, TIGIT inhibits immune responses meditated by both T cells and NK cells.8 The differential expression and action of the various immune checkpoints highlights their non-redundant, independent functions. Another feature of TIGIT which makes it an attractive target for immune checkpoint therapy is its high expression on TILs, but low expression in the periphery.5 Thus, targeting TIGIT can focus the immune response directly toward the target tumor while limiting systemic autoimmune reactions.

A better understanding of TIGITs localization, mechanism of action, and role in the cancer immunity cycle will inform the development of new anti-cancer immunotherapies. Greater understanding of TIGIT's function will also allow for design of complementary or synergistic combination therapies. TIGIT may be key in addressing the challenges of immune-associated toxicity, treatment resistance, and limited clinical utility of currently approved cancer immunotherapies. Results from clinical trials of anti-TIGIT antibodies are not yet available, but multiple trials are currently recruiting.10,11

Detection of human TIGIT (red) in FFPE human tonsil.
Detection of human TIGIT (red) in FFPE human tonsil. Antibody: Rabbit anti-TIGIT recombinant monoclonal [BLR047F] (A700-047). Secondary: Dylight 594 conjugated goat-anti-rabbit IgG (A120-101D4). Counterstain: DAPI (blue).
Detection of human TIGIT (yellow) in FFPE human tonsil.
Detection of human TIGIT (yellow) in FFPE human tonsil. Antibody: Rabbit anti-TIGIT recombinant monoclonal [BLR047F] (A700-047). Secondary: HRP-conjugated goat-anti-rabbit IgG (A120-501P). Substrate: Opal. Counterstain: DAPI (blue).
Detection of human TIGIT (red) in FFPE tonsil by IHC-IF.
Detection of human TIGIT (red) in FFPE tonsil by IHC-IF. Antibody: Rabbit anti-TIGIT recombinant monoclonal [BLR047F] (A700-047). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: Opal. Counterstain: DAPI (blue).

Highlighted TIGIT signal transduction pathways, related immunotherapy checkpoints and cell types involved in the immune-tumor microenvironment:

MarkerSignificanceBethyl Catalogue #
TIGITImmune checkpointi,iiA700-047
DNAM-1/CD226TIGIT ligand, T-cell cytotoxic activationxiv, iiiA700-063
PVR/CD155TIGIT ligand, T-cell cytotoxic repressionxiv,ivA700-074
CD96TIGIT regulation analogous to CD28/CTLA-4 mechanismvA700-065
TIM-3Influencing and alternate checkpointviA700-033
CEACAM1/5Cytotoxic activating ligand for TIM-3xixA700-032
PD-1Influencing and alternate checkpointxiv,vii,viiiA700-076
PDL-1Influencing and alternate checkpointxiv,ix,x,xxiA700-020
VISTAInfluencing and alternate checkpointxivA700-035
LAG3Influencing and alternate checkpointxivA700-027
FOXP3Regulator of TIGIT expression and activityxx,xA700-034
GranzymeMediator of T-cell apoptosisxiA700-022
MarkerCell TypeBethyl Catalogue #
CD3T-celli,iiA700-016
CD4+T-cellxxv,xxviA700-015
CD8+T-cellxxv,xxviA700-044
AHRTregxxv,xxviA700-118
CD56NK-cellxxv,xxviA700-152
CD19B-Cellxxv,xxviA700-137
CD20B-Cellxxv,xxviA500-017A
CD68, CD11bMacrophagexxv,xxviA500-018A, A700-107

[i] Ayush Pant, Ravi Medikonda, Michael Lim. 2020. Alternative Checkpoints as Targets for Immunotherapy. Curr Oncol Rep. 2020 Nov 3;22(12):126

[ii] H Harjunpää, C Guillerey. 2020. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020 May;200(2):108-119

[iii] Ralph Ja Maas, Janneke S Hoogstad-van Evert, Jolien Mr Van der Meer, Vera Mekers, Somayeh Rezaeifard, Alan J Korman, Paul Kjd de Jonge, Jeannette Cany, Rob Woestenenk, Nicolaas Pm Schaap, Leon F Massuger, Joop H Jansen, Willemijn Hobo, Harry Dolstra. 2020. TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer. Oncoimmunology. 2020 Nov 8;9(1):1843247

[iv] Ralph Ja Maas, Janneke S Hoogstad-van Evert, Jolien Mr Van der Meer, Vera Mekers, Somayeh Rezaeifard, Alan J Korman, Paul Kjd de Jonge, Jeannette Cany, Rob Woestenenk, Nicolaas Pm Schaap, Leon F Massuger, Joop H Jansen, Willemijn Hobo, Harry Dolstra. 2020. TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer. Oncoimmunology. 2020 Nov 8;9(1):1843247

[v] William C Dougall, Sema Kurtulus, Mark J Smyth, Ana C Anderson. 2017. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol Rev. 2017 Mar;276(1):112-120

[vi] Zhaoming Wang, George J Weiner. 2020. Immune checkpoint markers and anti-CD20-mediated NK cell activation. J Leukoc Biol. 2020 Dec 8

[vii] Chauvin JM, Zarour HM. 2020. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020 Sep;8(2)

[vii] Mahesh Yadav, Cherie Green, Connie Ma, Alberto Robert, Andrew Glibicky, Rin Nakamura, Teiko Sumiyoshi, Ray Meng, Yu-Waye Chu, Jenny Wu, John Byon, Joseph Woodard, Joanne Adamkewicz, Jane Grogan, Jeffrey M. Venstrom. 2016. Tigit, CD226 and PD-L1/PD-1 Are Highly Expressed By Marrow-Infiltrating T Cells in Patients with Multiple Myeloma. Blood (2016) 128 (22): 2102

[ix] Delvys Rodriguez-Abreu, Melissa Lynne Johnson, Maen A. Hussein, Manuel Cobo, Anjan Jayantilal Patel, Nevena Milica Secen, Ki Hyeong Lee, Bartomeu Massuti, Sandrine Hiret, James Chih-Hsin Yang, Fabrice Barlesi, Dae Ho Lee, Luis G. Paz-Ares, Robert Wenchen Hsieh, Karen Miller, Namrata Patil, Patrick Twomey, Amy V. Kapp, Raymond Meng, Byoung Chul Cho. 2020. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). Journal of Clinical Oncology 38(15_suppl):9503-9503

[x] Alicia N McMurchy, Jana Gillies, Maria Concetta Gizzi, Michela Riba, Jose Manuel Garcia-Manteiga, Davide Cittaro, Dejan Lazarevic, Sara Di Nunzio, Ignazio S Piras, Alessandro Bulfone, Maria Grazia Roncarolo, Elia Stupka, Rosa Bacchetta, Megan K Levings. 2013. A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells. Blood. Feb 21;121(8):1265-75

[xi] Ilia Voskoboinik, James C Whisstock, Joseph A Trapani. 2015. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. Jun;15(6):388-400.

[xii] Ceren Eyileten, Kinga Majchrzak, Zofia Pilch, Katarzyna Tonecka, Joanna Mucha, Bartlomiej Taciak, Katarzyna Ulewicz, Katarzyna Witt, Alberto Boffi, Magdalena Krol, Tomasz P Rygiel. 2016. Immune Cells in Cancer Therapy and Drug Delivery. Mediators Inflamm. 2016;2016: 5230219.

[xii] D Hammerl, M Smid, A M Timmermans, S Sleijfer, J W M Martens, R Debets. 2018. Breast cancer genomics and immuno-oncological markers to guide immune therapies. Semin Cancer Biol. 2018 Oct;52(Pt 2):178-188


References

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6. Chauvin JM, Pagliano O, Fourcade J, et al. 2015. TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. J Clin Invest. May;125(5):2046-58.

7. Marin-Acevedo JA, Dholaria B, Soyano AE, et al. 2018. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. Mar;11(1):39.

8. Zhang Q, Bi J, Zheng X, et al. 2018. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. Jun;19:723-32.

9. Anderson AC, Joller N, Kuchroo VK. 2016. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. May;44(5):989-1004.

10. Clinicaltrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). Accessed 2018 September 20. Available from: https://clinicaltrials.gov/ct2/show/NCT03119428.

11. Clinicaltrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). Accessed 2018 September 20. Available from: https://clinicaltrials.gov/ct2/show/NCT03563716.