Tim-3 suppresses the killing effect of Vγ9Vδ2 T cells on colon cancer cells by reducing perforin and granzyme B expression

Gamma delta (gamma delta) T cell-based tumor immunotherapy has been one of the most promising cancer immunotherapeutic strategies. However, the key regulators of the V gamma 9V delta 2 T cell-mediated antitumor response remain unclear. Recently, mounting reports have indicated that Tim-3 performs critical roles in the regulation of the activities of immune cells, including V gamma 9V delta 2 T cells. However, the roles of Tim-3 in V gamma 9V delta 2 T cell-mediated killing of colon cancer cells and the underlying mechanism remain largely unknown. Here, the proportion of Tim-3 + gamma delta T cells was significantly increased in both the peripheral blood and colon cancer tissue of patients and was significantly associated with TNM staging and tumor volume. Additionally, the activation of Tim-3 signaling significantly inhibited the killing efficiency of V gamma 9V delta 2 T cells against colon cancer cells. In addition, Tim-3 signaling reduced the expression of perforin and granzyme B in V gamma 9V delta 2 T cells. Blocking the perforin/granzyme B pathway also decreased the cytotoxicity of V gamma 9V delta 2 T cells to colon cancer cells. Moreover, Tim-3 signaling reduced the perforin and granzyme B expression of V gamma 9V delta 2 T cells in an ERK1/2 signaling pathway-dependent manner. This knowledge reveals that Tim-3 may be a promising therapeutic target to improve V gamma 9V delta 2 T cell-based adoptive immunotherapy for colon cancer.