Effector T cell responses unleashed by regulatory T cell ablation exacerbate oral squamous cell carcinoma

Abstract

Immune suppression by CD4⁺FOXP3⁺ regulatory T (Treg) cells and tumor infiltration by CD8⁺ effector T cells represent two major factors impacting response to cancer immunotherapy. Using deconvolution-based transcriptional profiling of human papilloma virus (HPV)-negative oral squamous cell carcinomas (OSCCs) and other solid cancers, we demonstrate that the density of Treg cells does not correlate with that of CD8⁺ T cells in many tumors, revealing polarized clusters enriched for either CD8⁺ T cells or CD4⁺ Treg and conventional T cells. In a mouse model of carcinogen-induced OSCC characterized by CD4⁺ T cell enrichment, late-stage Treg cell ablation triggers increased densities of both CD4⁺ and CD8⁺ effector T cells within oral lesions. Notably, this intervention does not induce tumor regression but instead induces rapid emergence of invasive OSCCs via an effector T cell-dependent process. Thus, induction of a T cell-inflamed phenotype via therapeutic manipulation of Treg cells may trigger unexpected tumor-promoting effects in OSCC.

Keywords: cancer immunology; oral squamous cell carcinoma; regulatory T cells.