Cd4 Depletion Potentiates Anti-Tumor Immunity Nin Adoptive Immunotherapy By Increasing Il-18r Alpha(Hi) Endogenous Cd8+T Cells

Abstract Adoptive T cell therapy (ACT) requires lympho-depletion pre-conditioning to eliminate immune-suppressive elements to allow for the efficient engraftment of adoptively transferred tumor-reactive T cells. Because anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells to enhance anti-tumor immunity, combinations of anti-CD4 treatment and ACT have synergistic potential in cancer therapy. We designed a post-ACT conditioning regimen that involves weekly treatment with anti-CD4 (CD4post). Using murine melanoma, cyclophosphamide and tumor-reactive CD8+ T cell infusion were included to represent an ACT model. We evaluated anti-tumor effects and immunologic changes of T cells. CD4post in ACT markedly increased tumor suppression and survival. Remarkably, CD4post worked differently on ex vivo primed CD8+ T cells versus endogenous CD8+ T cells. CD4post substantially increased the proliferation of ex vivo primed CD8+ T cells, while increasing endogenous CD8+ T cell differentiation and effector function. Endogenous CD8+ T cells upregulated activation/exhaustion markers and exhibited a skewed TCR repertoire, implying that CD4post boosted tumor-reactivity. Accordingly, CD4post-experienced endogenous CD8+ T cells showed enhanced intra-tumoral infiltration and exhibited greater anti-tumor activity against melanoma in vitro. Importantly, enrichment of the IL-18Rαhi subset was critical for boosting anti-tumor responses, as IL-18Rα+ cell-depletion CD8+ T cells resulted in diminished anti-tumor activity. This study highlights the clinical relevance of CD4post to ACT and gives insights into the characteristics of the immunological components that drive the augmented cancer–immunity cycle in ACT.