Tumor reactive æ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient

Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on conventional alpha beta T cells, the contribution of innate-like T cells such as gamma delta T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive gamma delta T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded gamma delta T cells in the blood and tumor after pembrolizumab treatment, and this V gamma 2V delta 1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral gamma delta T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade. Immune checkpoint blockade cancer therapy has been designed to enable tumor killing by conventional alpha beta T cells. Here authors show that in a Merkel cell carcinoma patient showing complete response to anti-PD-1 treatment, innate-like gamma delta T cells that specifically recognize the tumor cells expand, and likely contribute to therapeutic success.