gamma delta T cells are effectors of immune checkpoint blockade in mismatch repair-deficient colon cancers with antigen presentation defects

Abstract DNA mismatch repair deficient (MMR-d) cancers present an abundance of neoantigens that likely underlies their exceptional responsiveness to immune checkpoint blockade (ICB) 1,2 . However, MMR-d colon cancers that evade CD8 + T cells through loss of Human Leukocyte Antigen (HLA) class I-mediated antigen presentation 3–6 , frequently remain responsive to ICB 7 suggesting the involvement of other immune effector cells. Here, we demonstrate that HLA class I-negative MMR-d cancers are highly infiltrated by γδ T cells. These γδ T cells are mainly composed of Vδ1 and Vδ3 subsets, and express high levels of PD-1, activation markers including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors (KIRs). In vitro , PD-1 + γδ T cells, isolated from MMR-d colon cancers, exhibited a cytolytic response towards HLA class I-negative MMR-d colon cancer cell lines and β 2 - microglobulin ( B2M )-knockout patient-derived tumor organoids (PDTOs), which was enhanced as compared to antigen presentation-proficient cells. This response was diminished after blocking the interaction between NKG2D and its ligands. By comparing paired tumor samples of MMR-d colorectal cancer patients obtained before and after dual PD-1 and CTLA-4 blockade, we found that ICB profoundly increased the intratumoral frequency of γδ T cells in HLA class I-negative cancers. Taken together, these data indicate that γδ T cells contribute to the response to ICB therapy in patients with HLA class I-negative, MMR-d colon cancers, and illustrate the potential of γδ T cells in cancer immunotherapy.