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TIGIT and CD226: Tipping the Balance between Costimulatory and Coinhibitory Molecules to Augment the Cancer Immunotherapy Toolkit

2014; Cell Press; Volume: 26; Issue: 6 Linguagem: Inglês

10.1016/j.ccell.2014.11.016

1878-3686

Kristen E. Pauken, E. John Wherry,

Cancer Immunotherapy and Biomarkers

Combination therapies are becoming a focal point in cancer immunotherapy. In this issue of Cancer Cell, Johnston and colleagues identify the TIGIT/CD226 pathway, which provides significant interest for combination with PD-1 pathway blockade to improve anticancer CD8+ T cell responses, because it acts by a novel mechanism to regulate CD8+ T cell functions within the tumor microenvironment. Combination therapies are becoming a focal point in cancer immunotherapy. In this issue of Cancer Cell, Johnston and colleagues identify the TIGIT/CD226 pathway, which provides significant interest for combination with PD-1 pathway blockade to improve anticancer CD8+ T cell responses, because it acts by a novel mechanism to regulate CD8+ T cell functions within the tumor microenvironment. Recent advances in immunotherapy highlight the immune system’s ability to respond to many types of cancers. Unfortunately, endogenous antitumor immunity is typically inadequate to eradicate tumors. A dominant mechanism contributing to poor antitumor immunity is expression of inhibitory receptors including PD-1, CTLA-4, TIM-3, and LAG-3, which limit tumor-infiltrating CD8+ T cell functions. While blockade of PD-1 and/or CTLA-4 have shown significant clinical promise, most patients have not responded optimally, highlighting the need for additional approaches (Callahan and Wolchok, 2013Callahan M.K. Wolchok J.D. J. Leukoc. Biol. 2013; 94: 41-53Crossref PubMed Scopus (262) Google Scholar). In this issue of Cancer Cell, Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar identify the T cell coinhibitory receptor TIGIT (T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain) as an attractive candidate for coblockade with PD-1 pathway inhibitors to reverse CD8+ T cell dysfunction in cancer and chronic infection. TIGIT was identified by a genomic search for structures shared by other immunomodulatory receptors, including a conserved ITIM (Yu et al., 2009Yu X. Harden K. Gonzalez L.C. Francesco M. Chiang E. Irving B. Tom I. Ivelja S. Refino C.J. Clark H. et al.Nat. Immunol. 2009; 10: 48-57Crossref PubMed Scopus (808) Google Scholar). TIGIT is expressed by subsets of regulatory and memory CD4+ T cells, CD8+ T cells, and natural killer (NK) cells. TIGIT modulates NK cell killing and CD4+ T cell activation and promotes tolerance by increasing interleukin 10 (IL-10) while suppressing IL-12 production by dendritic cells (Stanietsky et al., 2013Stanietsky N. Rovis T.L. Glasner A. Seidel E. Tsukerman P. Yamin R. Enk J. Jonjic S. Mandelboim O. Eur. J. Immunol. 2013; 43: 2138-2150Crossref PubMed Scopus (161) Google Scholar, Yu et al., 2009Yu X. Harden K. Gonzalez L.C. Francesco M. Chiang E. Irving B. Tom I. Ivelja S. Refino C.J. Clark H. et al.Nat. Immunol. 2009; 10: 48-57Crossref PubMed Scopus (808) Google Scholar). The ligand for TIGIT is poliovirus receptor (PVR), which is shared with CD226, a costimulatory molecule important in antiviral and antitumoral responses (Gilfillan et al., 2008Gilfillan S. Chan C.J. Cella M. Haynes N.M. Rapaport A.S. Boles K.S. Andrews D.M. Smyth M.J. Colonna M. J. Exp. Med. 2008; 205: 2965-2973Crossref PubMed Scopus (245) Google Scholar, Welch et al., 2012Welch M.J. Teijaro J.R. Lewicki H.A. Colonna M. Oldstone M.B. Virology. 2012; 429: 163-170Crossref PubMed Scopus (23) Google Scholar). Thus, TIGIT is an important immunomodulator, but its role in CD8+ T cell responses and the molecular and functional relationships between TIGIT and CD226 have been unclear. Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar identified a critical role for TIGIT in regulating exhausted CD8+ T cell responses in tumors and chronic infection. TIGIT was associated with multiple human tumor types and was highly expressed on tumor-infiltrating lymphocytes (TILs) in CT26 and EMT6 tumor models. Despite high expression of PD-1 and TIGIT by a large fraction of TILs, single blockade of TIGIT or PD-L1, the main ligand for PD-1, had little effect on tumor volume or survival. Strikingly, however, coblockade of TIGIT and PD-L1 led to complete responses in the majority of mice and substantially improved survival. Mechanistically, coblockade improved intratumoral interferon γ (IFNγ) production, with no difference in the tumor-draining lymph node (LN). Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar also examined CD8+ T cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Here, TIGIT was important for modulating antiviral CD8+ T cell priming but played a less critical role in established exhausted CD8+ T cells. Importantly, combining TIGIT and PD-L1 blockade resulted in superior reversal of exhaustion and viral control than PD-L1 blockade alone (Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar). It is unclear why TIGIT blockade alone can promote cytokine production in tumors but not chronic infection, though differences in antiviral versus antitumor CD8+ T cell responses are likely to exist, including the severity of dysfunction, availability of ligands, degree of inflammation, and nature of systemic (e.g., LCMV) versus organ-specific (e.g., solid tumor) immune responses. More work is needed to understand the cellular and molecular mechanisms underlying this synergy. Inhibitory receptors may regulate T cell functions by different mechanisms, including (1) cell-intrinsic modulation via the receptor’s intracellular signaling domain(s), (2) indirect effects by competing with costimulatory receptors for shared ligands on APCs, and (3) modulating functions of the cells expressing ligand (Figure 1). Intriguingly, Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar found TIGIT’s immunomodulatory effects depend on CD226. TIGIT/CD226 competition for ligand could partially explain this dependence (Figure 1) (Yu et al., 2009Yu X. Harden K. Gonzalez L.C. Francesco M. Chiang E. Irving B. Tom I. Ivelja S. Refino C.J. Clark H. et al.Nat. Immunol. 2009; 10: 48-57Crossref PubMed Scopus (808) Google Scholar). However, here, TIGIT is shown to directly interact with CD226, where TIGIT prevents CD226 homodimerization (Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar) (Figure 1). TIGIT’s ability to interfere with CD226 signaling by physically preventing homodimerization rather than simply competing for ligand represents a novel mechanism by which inhibitory receptors can exert their immunomodulatory effects. This dynamic interplay is reminiscent of NK cell regulation, where signals from various activating and inhibitory receptors are summed, with the net determining whether the NK cells will execute their effector functions (Sun and Lanier, 2011Sun J.C. Lanier L.L. Nat. Rev. Immunol. 2011; 11: 645-657Crossref PubMed Scopus (479) Google Scholar). Importantly, blocking CD226 completely abrogated the effect of TIGIT/PD-L1 coblockade in the tumor but did not impact IFNγ-producing CD8+ T cell frequency in the tumor-draining LN compared to coblockade alone (Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar). These data suggest unique interplays among CD226, TIGIT, and PD-1 in the tumor microenvironment. While the precise mechanisms of T cell co-inhibition by PD-1 and TIGIT interactions remain to be fully defined, at a cellular level, (1) PD-1 and TIGIT could both modulate T cell functions in a cell-intrinsic manner; (2) PD-1 could signal into the T cell, while TIGIT-PVR interactions modulate PVR-expressing cell function; or (3) signals delivered into the ligand-expressing cell for both PD-1 and TIGIT could account for synergy in coblockade. At the molecular level, it will be important to determine if TIGIT’s ITIM contributes to its mechanism of action (Figure 1) and if this domain is needed for CD226 signal disruption. Additionally, it will be important to determine if sharing the same signaling domains has functional ramifications when multiple inhibitory receptors are acting simultaneously on the same cell (e.g., PD-1 and TIGIT both contain an ITIM). However, PD-1’s immunoreceptor tyrosine-based switch motif (ITSM) is thought to be the main signaling motif in T cells (Parry et al., 2005Parry R.V. Chemnitz J.M. Frauwirth K.A. Lanfranco A.R. Braunstein I. Kobayashi S.V. Linsley P.S. Thompson C.B. Riley J.L. Mol. Cell. Biol. 2005; 25: 9543-9553Crossref PubMed Scopus (1317) Google Scholar). In deciding which combination of receptors to block in patients, it will be important to determine whether blocking multiple receptors with the same signaling motifs has added benefit or if synergistic effects come from blocking receptors with distinct signaling motifs and/or modes of action. A key question underlying the mechanism of inhibitory receptor blockade for cancer immunotherapy is whether blockade acts on tumor-specific T cells within tumors, the secondary lymphoid organs, or both. Understanding this issue is essential to developing predictive biomarkers of immunotherapy and to determine the anatomical location best to perform biomarker assessment. This information will also be critical to determine the mechanisms involved in enhancing antitumor immunity. Johnston et al., 2014Johnston R.L. Comps-Agrar L. Hackney J. Yu X. Huseni M. Yang Y. Park S. Javinal V. Chiu H. Irving B. et al.Cancer Cell. 2014; 26 (this issue): 923-937Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar show that coblockade of PD-L1 and TIGIT boosted cytokine production by CD8+ T cells within the tumor microenvironment rather than in the tumor-draining LN. However, it is unclear whether the enhancement is restricted to TILs present in the tumor at the time of blockade or if immunotherapy drives CD8+ T cells from secondary lymphoid organs into tumors. Tumor-specific CD8+ T cells in the secondary lymphoid organs are likely less dysfunctional and retain higher proliferative potential than those within the tumor microenvironment, providing a potential reservoir that could contribute to responses following immunotherapy. Furthermore, previous work has shown that CD8+ T cells expressing the highest PD-1 levels preferentially reside in nonlymphoid tissues and are resistant to reversal of exhaustion by PD-1 pathway blockade alone, suggesting the need for a reservoir of less dysfunctional cells in lymphoid organs (Blackburn et al., 2008Blackburn S.D. Shin H. Freeman G.J. Wherry E.J. Proc. Natl. Acad. Sci. USA. 2008; 105: 15016-15021Crossref PubMed Scopus (375) Google Scholar, Paley et al., 2012Paley M.A. Kroy D.C. Odorizzi P.M. Johnnidis J.B. Dolfi D.V. Barnett B.E. Bikoff E.K. Robertson E.J. Lauer G.M. Reiner S.L. Wherry E.J. Science. 2012; 338: 1220-1225Crossref PubMed Scopus (577) Google Scholar). A better understanding of these population dynamics in tumor settings will be critical for designing and implementing optimal immunotherapy regiments. With combination therapy becoming central to immunotherapeutic approaches for cancer, selecting the right combination will be critical. Understanding how and when to block molecules such as TIGIT and PD-1 together, separately, or in combination with other targets will depend on deeper knowledge of expression patterns and underlying molecular mechanisms. Johnston et al.’s study on TIGIT highlights this pathway as one of substantial interest for further investigation. The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8+ T Cell Effector FunctionJohnston et al.Cancer CellNovember 26, 2014In BriefCheckpoint blockade has demonstrated success as a cancer immunotherapy strategy, but the limits of CTLA-4- and PD-1-blocking agents suggest the need for additional targets. Johnston et al. identify TIGIT as a coinhibitory receptor that critically limits antitumor CD8+ T cell-dependent immune responses Full-Text PDF Open Archive