733MO - γδT cells are effectors of immune checkpoint blockade in mismatch repair-deficient colon cancers with antigen presentation defects

Background

DNA mismatch repair deficient (MMR-d) cancers present an abundance of neoantigens that likely underlies their exceptional responsiveness to immune checkpoint blockade (ICB). Early evidence has indicated that MMR-d cancers that evade CD8⁺ T cells through loss of Human Leukocyte Antigen (HLA) class I-mediated antigen presentation still respond to ICB, suggesting compensatory responsiveness of other immune effector cells in this context.

Methods

We performed genomic, (single-cell) transcriptomic and imaging-based analyses of ICB-naïve and ICB-treated MMR-d cancers, including those from TCGA and the DRUP and NICHE clinical trials, complemented by in vitro experimentation, to identify effector cells of ICB in MMR-d cancers with B2M mutations.

Results

Paradoxically, B2M (b2-microglobulin) mutant MMR-d cancers in the DRUP study showed significantly enhanced responsiveness to ICB, also after adjustment for the tumor mutational burden (TMB) and primary tumour type. Across multiple cohorts, MMR-d cancers with B2M mutations consistently showed increased infiltration by gd T cells, whereas the levels of other effectors (including CD4⁺ and NK cells) remained unaffected. These gd T cells were mainly composed of Vd1 and Vd3 subsets, and expressed 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⁺ gd T cells, isolated from MMR-d colon cancers, exhibited a cytolytic response towards HLA class I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids (PDTOs), which was enhanced as compared to antigen presentation-proficient cells. By comparing paired tumour 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 gd T cells in HLA class I-negative cancers.

Conclusions

These data indicate that gd T cells are effectors of ICB therapy in patients with HLA class I-negative, MMR-d colon cancers. This underlines the potential of gd T cells in cancer immunotherapy, in particular for cancers with antigen presentation defects.

Clinical trial identification

NCT02925234.

Editorial acknowledgement

Legal entity responsible for the study

Emile E. Voest.

Funding

N.F.C.C.d.M. is funded by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 852832). E.E.V. received funding from the Oncode Institute and Open Targets (Identification of targets modulating lymphocyte-mediated tumour cell killing [Project ID: OTAR2061]; Project Leaders M. Garnett and E.E. Voest) and the Josephine Nefkens Foundation.

Disclosure

All authors have declared no conflicts of interest.