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.
© 2021. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antineoplastic Agents, Alkylating / pharmacology*
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CD4-Positive T-Lymphocytes / drug effects*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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Cyclophosphamide / pharmacology*
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Female
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Gene Expression Regulation, Neoplastic
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Immunotherapy, Adoptive / methods
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Interleukin-18 / genetics
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Interleukin-18 / immunology
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Interleukin-18 Receptor alpha Subunit / agonists
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Interleukin-18 Receptor alpha Subunit / genetics*
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Interleukin-18 Receptor alpha Subunit / immunology
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Lymphocyte Activation
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Melanoma, Experimental / genetics
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Melanoma, Experimental / immunology
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Melanoma, Experimental / mortality
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Melanoma, Experimental / therapy*
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Mice
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Mice, Inbred C57BL
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Receptors, CCR4 / genetics
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Receptors, CCR4 / immunology
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Receptors, CCR8 / genetics
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Receptors, CCR8 / immunology
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Receptors, Histamine H4 / genetics
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Receptors, Histamine H4 / immunology
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Signal Transduction
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Skin Neoplasms / genetics
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Skin Neoplasms / immunology
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Skin Neoplasms / mortality
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Skin Neoplasms / therapy*
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Survival Analysis
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / transplantation
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Tumor Burden / drug effects
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antineoplastic Agents, Alkylating
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Ccr4 protein, mouse
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Ccr8 protein, mouse
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Hrh4 protein, mouse
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Il18r1 protein, mouse
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Interleukin-18
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Interleukin-18 Receptor alpha Subunit
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Receptors, CCR4
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Receptors, CCR8
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Receptors, Histamine H4
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Cyclophosphamide