γδ T Cells: Friend or Foe in Melanoma under Immune Checkpoint Blockade?

Abstract

Immune checkpoint blockade was the first treatment to significantly prolong the survival of melanoma patients with distant metastases and nowadays has become standard of care. Therapeutic antagonistic antibodies targeting PD-1 block binding to its ligands and are able to reinvigorate exhausted T cells. However, PD-1 expression is not limited to αβ T cells, but can also be found on γδ T cells making this heterogeneous population of unconventional T cells a further target of anti-PD-1 therapy. Since γδ T cells are a less-well-studied T cell population, we looked into the pitfalls one might encounter when investigating these cells using polychromatic flow or mass cytometry, applying commercially available kits for magnetic cell isolation or when performing immunohistochemical staining. In this context, a careful selection of the utilized antibodies is of particular importance in order to avoid bias in the phenotypic or functional characterization and the drawn conclusions. Furthermore, we adapted an assay developed for αβ T cells to the γδ T cell subset, allowing a more rapid detection of functional Vδ1 and Vδ2 T cells based on the assessment of integrin activation. In addition to that we implemented the identification of γδ T cells in a high dimensional in situ imaging approach. This enables in-depth investigation of the phenotypic profile of tissue-resident and tumor-infiltrating innate-like Vγ9Vδ2 and adaptive-like Vδ1 T cells and their microenvironment. Building on this, future studies might elucidate the role and interplay of γδ T cells in solid malignancies and uncover potential targets of immunotherapy. In parallel, we examined the role of γδ T cells in late-stage melanoma patients undergoing anti-PD-1 therapy, since a durable response is only achieved in a fraction of patients. Peripheral blood mononuclear cells and tumor-infiltrating lymphocytes were used to study the phenotype, functionality and TCR repertoire of Vδ1 and Vδ2 T cells. High frequencies of peripheral Vδ1 T cells were linked to poor overall survival and a late-differentiated potentially senescent-like phenotype that is presumably not responsive to immune checkpoint blockade. However, the abundance of Vδ1 T cells in the tumor was linked to prolonged overall survival and the senescent-like phenotype showed a lower prevalence at the tumor site. This supports the currently ongoing endeavors taking advantage of Vδ1 T cells for cancer immunotherapy.

Die Dissertation ist bis zum 21. Januar 2026 gesperrt !