Immunotherapy using immune checkpoint blockade (ICB) is considered to mainly benefit patients by activating anti-tumour CD8+ T cell responses. A recent study in Nature shows that γδ T cells are also potently activated by ICB and that subsets of PD1+ Vδ1 and Vδ3 T cells are particularly important for responding to ICB in cancers that have downregulated MHC class I expression.
To explore this, the authors examined responses to anti-PD1 ICB in a cohort of 70 patients with MMR-d tumours that were wild type (B2MWT) or mutant/ deficient (B2MMUT) with respect to β2-microglobulin expression. Of note, a clinical benefit of anti-PD1 ICB was noted in 95% of patients with B2MMUT tumours compared with in 62% of patients with B2MWT tumours. Transcriptomic analyses of MMR-d cancer in patients with colon, stomach and endometrium carcinomas indicated that expression levels of TRDV1 and TRDV3 (which encode the variable regions of the δ1 and δ3 chains of the γδ T cell receptor) and of genes encoding killer cell immunoglobulin-like receptors (KIRs) — which regulate γδ T cell activity — were markedly upregulated in patients with B2MMUT compared with B2MWT cancers. Single-cell RNA-sequencing analysis of γδ T cells isolated from five MMR-d colon cancers indicated the presence of three distinct subsets; Vδ1 T cells were the most prevalent followed by Vδ2 and then Vδ3 T cells. Previous studies have suggested that the Vδ1 and Vδ3 subsets are mainly ‘tissue resident’ at mucosal sites and that Vδ2 γδ T cells are predominantly found in the blood. The Vδ1 and Vδ3 T cells showed highest expression of PD1, KIRs and other activating receptors, whereas almost all γδ T cells expressed the genes encoding the cytotoxic mediators granzyme B, granulysin and perforin. Consistent with this, when γδ T cells were isolated from MMR-d colon cancers, expanded in vitro and co-cultured with different cancer cell lines, reactivity against cancer cells was largely restricted to the PD1+ γδ T cells (which comprised Vδ1 and Vδ3 T cells). Further experiments indicated that β2-microglobulin loss increases the sensitivity of cancer cells to γδ T cell-mediated cytotoxicity and a key role was also identified for the NKG2D receptor, as blocking its ligands on MMR-d cancer cells reduced killing activity by γδ T cells.
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