In the last 15 years, the landscape of immunotherapy for skin cancer has dramatically evolved, with new, targeted therapies emerging that specifically modulate the behavior and phenotype of various immune subsets. This has underscored the critical need to identify new immune populations that suppress skin cancer, expanding our capabilities in combating this disease.
A key focus of our research has been the double-positive CD4/CD8αβ (DPαβ) T cells, which are prevalent in peripheral tissues and increase in number during cancer progression. The role of these cells in cancer has been controversial. Our team has developed a novel method that achieves high purity in isolating these cells; 98% of what were previously considered unsorted DPαβ T cells were aggregates of single positive cells. We first explored whether the co-expression of CD4 and CD8αβ markers was due to transient activation. Our studies involving transferring DPαβ T cells into immunodeficient Rag1-/- mice, which lack both B cells and T cells, revealed that these cells were not only detectable three months later, but also maintained a stable phenotype, suggesting a capacity for self-renewal. Further investigation into the origin of DPαβ T cells revealed that when single-positive (SP) CD4 T cells were transferred into Rag1-/- mice, they began expressing CD8αβ in a T cell receptor-dependent manner, indicating that peripheral DPαβ T cells likely originate from tissue-resident CD4+ T cells, rather than from CD8αβ T cells. Notably, single-cell sequencing of DPαβ T cells from skin-draining lymph nodes showed that approximately 40% expressed FOXP3, a marker typically associated with immunosuppressive regulatory T cells (Tregs). This finding suggests that DPαβ T cells might possess an immunosuppressive phenotype. Supporting this, in contact hypersensitivity assays, activated DPαβ T cells significantly dampened the response of skin CD8+ T cells, further confirming their role in immune suppression.
These insights highlight the potential of targeting newly characterized DPαβ T cells as an effective therapeutic strategy in skin cancer treatment, paving the way for novel interventions that could enhance patient outcomes.