Editors' ChoiceCancer Immunology

Shifting T Cells into Action

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Science Signaling  23 Dec 2014:
Vol. 7, Issue 357, pp. ec353
DOI: 10.1126/scisignal.aaa5276

The immune system is often ineffective at eliminating tumor cells. Like a chronic infection, cancer can induce T cell exhaustion, rendering T cells inactive. The abundance of coinhibitory receptors on exhausted T cells is typically high. Functionally blocking these receptors, including programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), have some clinical benefit, but the lack of optimal responses suggest that additional or possibly combined therapeutic approaches are needed (see Pauken and Wherry). Johnston et al. found that targeting an additional coinhibitory receptor called TIGIT (T cell immunoglobulin and ITIM domain) enhanced the antitumor and antiviral activity of CD8+ T cells in mice receiving anti-PD-1 therapy. Compared with T cells from healthy donors or patient-matched circulating T cells, T cells infiltrating tumors in patients with nonsmall cell lung cancer had greater abundance of TIGIT, which correlated with the abundance of PD-1. Mice bearing CD26 colon carcinomas treated with a combination of function-blocking antibodies against TIGIT and PD-1 or its ligand PD-L1 exhibited durable tumor regression. Mice that received the combination therapy and cleared their CT26 cell-derived tumors mounted an immune response when inoculated with new CT26 cells but not with EMT6 mammary carcinoma cells, indicating that treated mice developed tumor antigen-specific immunity. Depleting CD8+ T cells prevented the antitumor response to combined therapy. Coinhibitory receptors can suppress T cell function directly through intracellular mechanisms or indirectly (as does CTLA-4) by inhibiting costimulatory receptors. Time-resolved fluorescence energy transfer (TR-FRET) of mouse CD8+ T cells revealed that TIGIT competed with the costimulatory receptor CD226 for a shared ligand, PVR, and physically prevented CD226 homodimerization. Functionally blocking CD226 prevented combination therapy-induced tumor regression in mice. As in the mouse tumor models, TIGIT had a similar role in suppressing CD8+ T cell function in chronic viral infection models. Mice with T cell-specific deletion of TIGIT (TIGITfl/fl/CD4cre) showed normal T cell development and response to acute infection with lymphocytic choriomeningitis virus (LCMV), but had enhanced T cell responses to chronic LCMV infection. Furthermore, in wild-type mice with existing LCMV infection, treatment with a TIGIT-blocking antibody was ineffective by itself but enhanced the antiviral effects of the PD-1-blocking antibody, suggesting that TIGIT blockade is ineffective against already exhausted T cells. As in the tumor model, blocking CD226 prevented the antiviral effects of combined therapy. Together, the findings suggest that combination therapy targeting PD-1 (or PD-L1) and TIGIT might improve immune system function in patients with cancer or chronic viral infection by enabling stimulatory signaling in T cells.

R. J. Johnston, L. Comps-Agrar, J. Hackney, X. Yu, M. Huseni, Y. Yang, S. Park, V. Javinal, H. Chiu, B. Irving, D. L. Eaton, J. L. Grogan, The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014). [PubMed]

K. E. Pauken, E. J. Wherry, TIGIT and CD226: Tipping the balance between costimulatory and coinhibitory molecules to augment the cancer immunotherapy toolkit. Cancer Cell 26, 785–787 (2014). [PubMed]

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