Despite advances in cancer immunotherapy, immunosuppression mediated by regulatory T cells (Tregs) remains a major barrier to effective anti-tumour immunity, with high Treg abundance being associated with poor prognosis across many cancer types. Therefore, Tregs resemble an appealing target for cancer immunotherapy, whereas their essential role in maintaining immune homeostasis renders systemic depletion an unfavourable strategy.
To address this challenge, we aimed to identify features specific to tumour-infiltrating Tregs (tiTregs). We performed single-cell RNA and TCR sequencing of CD4⁺ T cells from a variety of preclinical tumour models, encompassing 13 different tissue and tumour types. Our analysis revealed that tiTregs exhibit a tumour-specific transcriptome that is primarily shaped by the tissue microenvironment rather than by tumour origin. We also found that the majority of tiTregs is recruited from draining lymph nodes (dLNs), rather than the adjacent tissues or through de novo upregulation of Foxp3 in conventional CD4⁺ T cells. Notably, we identified a distinct subset of tiTregs with stem-like properties and a highly proliferative phenotype, inferred to be a precursor population for diverse tiTreg subsets. This precursor population displayed a transcriptomic profile reminiscent of perinatal Tregs (pnTregs), a long-lived Treg population established early in life that is essential for preventing systemic autoimmunity. Within pn-like tiTregs, the pro-survival gene Birc5 (encoding Survivin) was found to be highly specific and conserved across murine and human tumours. Interestingly, Treg-specific deletion of Birc5 led to severe autoimmunity in early life, underscoring its critical role in bona fide pnTregs. However, conditional ablation of Birc5 in adult mice did not induce autoimmunity but resulted in a failure of Tregs to expand within tumours, thereby significantly enhancing anti-tumour immunity.
In summary, we identified key features of tumour-infiltrating Tregs and propose Survivin as a promising target in Tregs to boost anti-tumour immunity without compromising systemic immune tolerance.