Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rαhi CD8+ T cells
Seon-Hee Kim, Eun‐Jung Cho, Yu I. Kim, Chungyong Han, Beom K. Choi, Byoung S. Kwon
Abstract
Abstract 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.