γδ T Cells Mediate Immunotherapy Response in HLA Class I–Deficient Cancers

Clinical benefit from immune checkpoint blockade (ICB) is strongly linked to tumor neoantigen presentation and CD8⁺ T-cell responses, making mismatch repair–deficient (MMR-d) cancers attractive targets for these therapies. Paradoxically, MMR-d cancers lacking expression of β2-microglobulin (B2M), a human leukocyte antigen class I (HLA-I) gene, still respond to ICB, suggesting that antigen recognition by CD8⁺ T cells is not the only requirement for therapeutic efficacy. In this study, de Vries, van de Haar, Veninga, Chalabi, and colleagues investigated the role of HLA-I–unrestricted immune cell subsets in mediating the response to ICB in MMR-d cancers and showed that tumors with B2M inactivation (B2M^MUT) experienced significant clinical benefit from PD-1 blockade. Analysis of data from The Cancer Genome Atlas revealed that B2M^MUT MMR-d tumors had elevated expression of TRDV1 and TRDV3, which encode chains of the γδ T-cell receptor, as well as killer-cell immunoglobulin-like receptors (KIR). Further analysis of γδ T cells isolated from patients with MMR-d colon cancers revealed they consisted predominantly of activated Vδ1 and Vδ3 T cells expressing PD-1, KIR, and cytotoxic effectors, and evaluation of the ability of these tumor-infiltrating γδ T cells to kill cancer cells indicated that PD-1⁺ Vδ1 and Vδ3 T cells induced higher levels of apoptosis in HLA-I^– colon cancer cells compared with HLA-I⁺ cells, which supports the increased sensitivity of HLA-I^– colon cancer cells to γδ T cell–mediated killing. Additionally, blockade of the activating receptor NKG2D was able to inhibit the cytotoxic activity of PD-1⁺ γδ T cells, suggesting the partial dependence of this phenotype on NKG2D/NKG2D–ligand interactions. Finally, in a therapeutic context, ICB treatment promoted higher γδ T-cell infiltration in B2M^MUT tumors compared to wild-type B2M tumors. In conclusion, this study demonstrated the importance of γδ T-cell function in the response to ICB in MMR-d cancers, especially those lacking HLA-I expression.

de Vries NL, van de Haar J, Veninga V, Chalabi M, Ijsselsteijn ME, van der Ploeg M, et al. γδ T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature 2023;613:743–50.

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