| First Author | Kim SH | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 5314 |
| PubMed ID | 34493727 | Mgi Jnum | J:337117 |
| Mgi Id | MGI:6787715 | Doi | 10.1038/s41467-021-25559-7 |
| Citation | Kim SH, et al. (2021) Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Ralpha(hi) CD8(+) T cells. Nat Commun 12(1):5314 |
| abstractText | 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-18Ralpha(hi) CD8(+) T cell subset is the key event in CTX(pre)/CD4(post)-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Ralpha(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. |
