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 (CD4post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTXpre), CD4post, and ex vivo primed tumor-reactive CD8+ T-cell infusion is presented. CTXpre/CD4post 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-18Rαhi CD8+ T cell subset is the key event in CTXpre/CD4post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rαhi subset is mediated by IL-18 signaling and TCR–MHC I interaction. This study highlights the clinical relevance of CD4post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8+ T cells.
Highlights
Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells
We show that CTXpre/CD4post accelerates the proliferation and effector function of ex-T and en-T cells by enriching the IL18Rαhi CD8+ T-cell subset, which is the key for increasing antitumor responses
Not observed in the other groups, the group treated by ACT in the presence of CTXpre/CD4post (CTX/ex-T/anti-CD4 group) developed vitiligo, a sign of CD8+ T-cell-induced melanocyte destruction[6,7], indicating the increased response of CD8+ T cells (Fig. 1e, f)
Summary
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+ immunesuppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. As the anti-CD4 antibody depletes CD4-expressing cytokine sinks[3,15], adequate treatment after preconditioning in ACT has the potential to induce synergistic anti-tumor responses by enhancing the activity of ex-T cells and endogenous CD8+ T cells (en-T cells; a newly repopulating subset after lymphodepletion). We demonstrate that the application of anti-CD4 as a post-conditioning regimen (CD4post; transient CD4 depletion after ex-T-cell transfer), in combination with cyclophosphamide preconditioning (CTXpre), considerably enhances ACT efficacy. We further reveal the characteristics of the IL18Rαhi CD8+ T-cell population and its generative mechanism in the CTXpre/CD4post regimen
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