Good news! Cancer is history (soon)!
"We know that CD8+ T cells contribute to the effect of immunotherapy on cancer — but researchers have now discovered that γδ T cells are also at work. Researchers compared colon cancers that had been exposed to an immunotherapy called immune checkpoint inhibitors with tumours that did not receive this treatment. The γδ T cells helped the immunotherapy to work in a kind of tumour that lacks the conventional immune response involving CD8+ T cells. γδ T cells have emerged as a viable and promising approach for cancer immunotherapy in recent years."
From the abstract and key points:
"Current cancer immunotherapies are primarily predicated on αβ T cells, with a stringent dependence on MHC-mediated presentation of tumour-enriched peptides or unique neoantigens that can limit their efficacy and applicability in various contexts. After two decades of preclinical research and preliminary clinical studies involving very small numbers of patients, γδ T cells are now being explored as a viable and promising approach for cancer immunotherapy. The unique features of γδ T cells, including their tissue tropisms, antitumour activity that is independent of neoantigen burden and conventional MHC-dependent antigen presentation, and combination of typical properties of T cells and natural killer cells, make them very appealing effectors in multiple cancer settings. ...
Key points
- Human γδ T cells comprise subsets with distinct tissue tropisms: Vδ1+ cells are enriched in mucosal tissues (and often predominate within carcinomas), whereas Vδ2+ cells are most abundant in the blood and lymphoid organs.
- Most human γδ T cells have antitumour functions, but have also been reported to have pro-tumour properties in specific contexts.
- γδ T cells have prognostic value in patients with cancer, being associated with favourable outcomes for most tumour types, especially when focusing on Vδ1+ cells.
- γδ T cells are endowed with antitumour mechanisms of both αβ T cells and natural killer (NK) cells, mediated not only by T cell receptor (TCR) and co-stimulatory signals but also by activating NK cell receptors.
- γδ T cells mostly act in a manner independent of MHC class I-mediated antigen presentation, making them suitable for treatment of MHC class I-deficient tumours, as well as for application in allogeneic settings.
- Emerging therapeutic approaches based on γδ T cells comprise cell engagers, adoptive transfer of expanded Vδ1+ or Vδ2+ T cell subsets, and genetic engineering of γδ T cells to express chimeric antigen receptors (CARs) or αβ T cells to express specific γδTCRs."
From the abstract:
"DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB). Here, in contrast to other cancer types, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of β2-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8+ T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by γδ T cells in MMR-d cancers. These γδ T cells mainly comprised the Vδ1 and Vδ3 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1+ γδ T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of γδ T cells in B2M-deficient cancers. Taken together, these data indicate that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of γδ T cells in cancer immunotherapy."
Extended Data Fig. 5: Phenotype and reactivity of γδ T cells towards cancer cell lines
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