Deciphering TIGIT’s role in immune response
Expert opinion
When a chronic infection or malignant tumor develops, the body’s ensuing immune struggle may lead to an immune response overflow. The balance between the costimulatory and coincident immune response may be impaired so ways to properly recharge the immune cells at the tumor site could restore their ability to effectively fight the spread of the disease. T cells play a critical role in cancer immunity. Effective recruitment and infiltration at the tumor site are altered as cancer cells up-regulate a wide range of cancer mechanisms. Their defense is to suppress the T cells’ ability to reach the tumor and trigger curative responses to infiltration.
Over the past decade, many therapeutic approaches aiming to reactivate immune response by blocking inhibitory tumoral response at critical immune checkpoints, mediated by PD-1/PDL1 for example, appear to be very promising for efficient treatment. Many other molecules involved in this regulation balance have been identified but, for many of them, the mechanism of action remains unclear.
In this article, Robert J. Johnston demonstrates how TIGIT is involved in regulating tumor infiltrating CD8+ T cells. Using recombinant CHO-cells expressing tagged TIGIT and CD226 receptors, he shows that TIGIT could disrupt CD226 homodimerization and inhibit downstream signals. This hypothesis was further documented with human T cells in vitro, and in xenograft mice models in vivo. He provides a full demonstration that TIGIT suppression of CD8+ T cell responses is dependent on CD226.
Here is a new path for different immunotherapies and combinatorial treatment strategy approaches that allow the immune system to overcome tumor barriers for enhanced anti-cancer action and improved patient outcome.
Abstract
Tumors constitute highly suppressive microenvironments in which infiltrating T cells are “exhausted” by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT’s complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.