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

de Vries et al. (BioRxiv) doi: 10.1101/2021.10.14.464229

Keywords

  • DNA mismatch repair deficient (MMR-d) cancers

  • γδ T cells

  • Immune checkpoint blockade

 

Main Findings

DNA mismatch repair deficient (MMR-d) cancers present neoantigens to T cells and are responsiveness to immune checkpoint blockade. However, MMR-d colon cancers that evade CD8+ T cells through loss of HLA class I-mediated antigen presentation remain responsive to immune checkpoint blockade and these mechanisms remain unclear. Here, the authors show that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA class I-negative, MMR-d colon cancers. First, they show that HLA class I-negative MMR-d cancers are highly infiltrated by γδ T cells. These γδ1 and 3 T cell subsets express PD-1 and cytotoxic molecules. Then, they performed cytotoxic assays showing that PD-1+ γδ T cells kill HLA-I negative MMR-d colon cancer cell lines and organoids. Finally, in a clinical context, they emphasized that PD-1 and CTLA-4 blockade increased the intratumoral frequency of γδ T cells in HLA class I-negative cancers. 

Limitations

  • The authors may more discuss the role of other HLA class I-independent immunes cells (ILCs, CD4+ T cells, macrophages) in MMR-d cancers with immune checkpoint blockade.

  • More replicates are needed for functional experiments to have robust statistical tests.

  • The authors may also more discuss the immunosuppression by γδ T cells in other cancers.

Significance/Novelty

The authors show that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA class I-negative, MMR-d colon cancers, and illustrate the potential of γδ T cells in cancer immunotherapy. The authors should more discuss the fact that γδ T cells have been linked to responses to immune checkpoint blockade in other cancers before (for example follicular lymphoma). To better assess that these cells are critical, the authors may work more on their functional assays to have more replicates and perform robust statistical tests. It would also be of interest to investigate if other HLA class I-independent immunes cells (ILCs, CD4+ T cells, macrophages) are effectors of immune checkpoint blockade in MMR-d colon cancers with antigen presentation defects, and to discuss their interactions with γδ T cells.

 

Credit

Reviewed by Guillaume Mestrallet as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.