Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy
Background Overcoming immune suppression is a major barrier to eliciting potent CD8+ T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4+Foxp3+ regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e010170.full |
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| author | Keisuke Shirai Tiffany Chen Mary Jo Turk Delaney E Ramirez Christo P C Dragnev Tyler G Searles Nathaniel Spicer J Louise Lines Aaron R Hawkes Wilson L Davis Asmaa Mohamed Joseph D Phillips Pamela C Rosato Yina H Huang |
| author_facet | Keisuke Shirai Tiffany Chen Mary Jo Turk Delaney E Ramirez Christo P C Dragnev Tyler G Searles Nathaniel Spicer J Louise Lines Aaron R Hawkes Wilson L Davis Asmaa Mohamed Joseph D Phillips Pamela C Rosato Yina H Huang |
| author_sort | Keisuke Shirai |
| collection | DOAJ |
| description | Background Overcoming immune suppression is a major barrier to eliciting potent CD8+ T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4+Foxp3+ regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early clinical trials. However, the underlying basis for treatment efficacy, more specifically the implications of codepleting other CD4-expressing cell compartments in tumor-bearing hosts, is not well understood.Methods Tumor-bearing mice were treated with anti-CD4 versus other therapies that preserve helper T cell function, and the priming, tissue distribution, and maintenance of tumor antigen-specific CD8 T cells were assessed. Antibody blockade and transgenic mouse models were used to determine the mechanisms of CD8 T cell priming. Single-cell RNA-sequencing (scRNAseq) was used to further characterize CD8 T cells that are primed by anti-CD4 therapy and to identify immunosuppressive CD4 T cell subsets in human melanoma following immune checkpoint blockade (ICB).Results Comparing anti-CD4 to dual ICB therapy, we show that anti-CD4 facilitates more robust priming of TCF-1+, IL-2-producing, tumor-specific CD8+ T cells that disseminate to tissues and form memory. By decoupling priming from homeostatic proliferation and associated cytokines, we find that anti-CD4 functions independently of creating homeostatic space for CD8+ T cells. We also show that depletion of CD4-expressing antigen-presenting cell subsets is not required for anti-CD4 efficacy. Instead, robust tumor-specific CD8+ T cell priming and memory generation required the removal of total antigen-specific CD4+ T cells, including both Tregs and CD4+ Foxp3-negative conventional (Tconv) cells. In particular, the elimination of CD4+ Tconv cells was necessary for the accumulation and maturation of conventional type-1 dendritic cells in tumor-draining LNs, which were required for CD8+ T cell priming. Accordingly, anti-CD4 treatment restored CD8+ T cell responses in mice cotreated with dual ICB. scRNAseq of melanoma tumors from patients who received ICB revealed the presence of Tr1 and Treg subsets, as well as CD4+ Tconv subsets that lacked clear transcriptional evidence of helper differentiation.Conclusions These findings underscore the underappreciated benefit of depleting CD4+ Tconv cells to promote systemic primary and memory CD8+ T cell responses against cancer. |
| format | Article |
| id | doaj-art-8a59c2f71d024d7c9006dc8599fb23b3 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-8a59c2f71d024d7c9006dc8599fb23b32025-08-20T03:48:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-010170Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapyKeisuke Shirai0Tiffany Chen1Mary Jo Turk2Delaney E Ramirez3Christo P C Dragnev4Tyler G Searles5Nathaniel Spicer6J Louise Lines7Aaron R Hawkes8Wilson L Davis9Asmaa Mohamed10Joseph D Phillips11Pamela C Rosato12Yina H Huang13Aff7 grid.259828.c0000000121893475Division of Hematology/OncologyMedical University of South Carolina 173 Ashley Ave., Basic Science Building, Suite 102 29425 Charleston SC USA1 Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USADepartment of Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADartmouth Cancer Center, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADartmouth Cancer Center, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADepartment of Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADartmouth Cancer Center, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADartmouth Cancer Center, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADartmouth Cancer Center, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADepartment of Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADartmouth Cancer Center, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADepartment of Microbiology and Immunology, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USABackground Overcoming immune suppression is a major barrier to eliciting potent CD8+ T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4+Foxp3+ regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early clinical trials. However, the underlying basis for treatment efficacy, more specifically the implications of codepleting other CD4-expressing cell compartments in tumor-bearing hosts, is not well understood.Methods Tumor-bearing mice were treated with anti-CD4 versus other therapies that preserve helper T cell function, and the priming, tissue distribution, and maintenance of tumor antigen-specific CD8 T cells were assessed. Antibody blockade and transgenic mouse models were used to determine the mechanisms of CD8 T cell priming. Single-cell RNA-sequencing (scRNAseq) was used to further characterize CD8 T cells that are primed by anti-CD4 therapy and to identify immunosuppressive CD4 T cell subsets in human melanoma following immune checkpoint blockade (ICB).Results Comparing anti-CD4 to dual ICB therapy, we show that anti-CD4 facilitates more robust priming of TCF-1+, IL-2-producing, tumor-specific CD8+ T cells that disseminate to tissues and form memory. By decoupling priming from homeostatic proliferation and associated cytokines, we find that anti-CD4 functions independently of creating homeostatic space for CD8+ T cells. We also show that depletion of CD4-expressing antigen-presenting cell subsets is not required for anti-CD4 efficacy. Instead, robust tumor-specific CD8+ T cell priming and memory generation required the removal of total antigen-specific CD4+ T cells, including both Tregs and CD4+ Foxp3-negative conventional (Tconv) cells. In particular, the elimination of CD4+ Tconv cells was necessary for the accumulation and maturation of conventional type-1 dendritic cells in tumor-draining LNs, which were required for CD8+ T cell priming. Accordingly, anti-CD4 treatment restored CD8+ T cell responses in mice cotreated with dual ICB. scRNAseq of melanoma tumors from patients who received ICB revealed the presence of Tr1 and Treg subsets, as well as CD4+ Tconv subsets that lacked clear transcriptional evidence of helper differentiation.Conclusions These findings underscore the underappreciated benefit of depleting CD4+ Tconv cells to promote systemic primary and memory CD8+ T cell responses against cancer.https://jitc.bmj.com/content/12/11/e010170.full |
| spellingShingle | Keisuke Shirai Tiffany Chen Mary Jo Turk Delaney E Ramirez Christo P C Dragnev Tyler G Searles Nathaniel Spicer J Louise Lines Aaron R Hawkes Wilson L Davis Asmaa Mohamed Joseph D Phillips Pamela C Rosato Yina H Huang Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy Journal for ImmunoTherapy of Cancer |
| title | Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy |
| title_full | Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy |
| title_fullStr | Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy |
| title_full_unstemmed | Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy |
| title_short | Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy |
| title_sort | depletion of conventional cd4 t cells is required for robust priming and dissemination of tumor antigen specific cd8 t cells in the setting of anti cd4 therapy |
| url | https://jitc.bmj.com/content/12/11/e010170.full |
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