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

Autor: Kim SH; Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea.; Department of Biomedical Laboratory Science, Catholic Kwandong University, Gangneung, Republic of Korea., Cho E; Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea., Kim YI; Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea., Han C; Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea. chungyong.han27@gmail.com.; Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea. chungyong.han27@gmail.com., Choi BK; Biomedicine Production Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea. 11380@ncc.re.kr., Kwon BS; Eutilex Institute for Biomedical Research, Eutilex Co., Ltd, Seoul, Republic of Korea. bskwon@eutilex.com.; Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA. bskwon@eutilex.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Sep 07; Vol. 12 (1), pp. 5314. Date of Electronic Publication: 2021 Sep 07.
DOI: 10.1038/s41467-021-25559-7
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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