Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rα^hi CD8⁺ T...

Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4⁺ immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4^post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTX^pre), CD4^post, and ex vivo primed tumor-reactive CD8⁺ T-cell infusion is presented. CTX^pre/CD4^post increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8⁺ T cells and endogenous CD8⁺ T cells. Endogenous CD8⁺ T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rα^hi CD8⁺ T cell subset is the key event in CTX^pre/CD4^post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rα^hi subset is mediated by IL-18 signaling and TCR-MHC I interaction. This study highlights the clinical relevance of CD4^post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8⁺ T cells.