ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/084/SRR25247884/SRR25247884.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/078/SRR25247878/SRR25247878_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/080/SRR25247880/SRR25247880_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/082/SRR25247882/SRR25247882_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/078/SRR25247878/SRR25247878.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/077/SRR25247877/SRR25247877_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/084/SRR25247884/SRR25247884_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/080/SRR25247880/SRR25247880.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/083/SRR25247883/SRR25247883.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/079/SRR25247879/SRR25247879_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/079/SRR25247879/SRR25247879.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/076/SRR25247876/SRR25247876.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/087/SRR25247887/SRR25247887.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/077/SRR25247877/SRR25247877_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/076/SRR25247876/SRR25247876_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/086/SRR25247886/SRR25247886_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/085/SRR25247885/SRR25247885_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/083/SRR25247883/SRR25247883_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/080/SRR25247880/SRR25247880_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/082/SRR25247882/SRR25247882_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/084/SRR25247884/SRR25247884_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/078/SRR25247878/SRR25247878_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/081/SRR25247881/SRR25247881.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/076/SRR25247876/SRR25247876_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/087/SRR25247887/SRR25247887_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/086/SRR25247886/SRR25247886.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/082/SRR25247882/SRR25247882.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/086/SRR25247886/SRR25247886_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/075/SRR25247875/SRR25247875.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/075/SRR25247875/SRR25247875_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/087/SRR25247887/SRR25247887_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/085/SRR25247885/SRR25247885_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/081/SRR25247881/SRR25247881_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/081/SRR25247881/SRR25247881_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/083/SRR25247883/SRR25247883_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/077/SRR25247877/SRR25247877.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/079/SRR25247879/SRR25247879_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/075/SRR25247875/SRR25247875_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/085/SRR25247885/SRR25247885.fastq.gzprimaryOK200GenomicsRoychoudhuri Laboratory, Department of Pathology, University of Cambridgehttps://www.ebi.ac.uk/ena/browser/view/PRJNA994054Mus musculusxref:PubMed:38100544Regulatory T (Treg) cells are essential for immune homeostasis but inhibit immune rejection of cancer. Strategies to disrupt Treg-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for this failure are poorly understood. By modeling Treg-targeted immunotherapy in mice, we find that a subset of CD4+ Foxp3- conventional T (Tconv) cells with potent suppressive function undergoes activation and expansion upon depletion of Foxp3+ Treg cells and limits therapeutic efficacy. We noted that Foxp3- Tconv cells within tumors adopt a Treg-like transcriptional profile upon Treg depletion and acquire suppressive function. This is attributable to a Th2-like subset of CD4+ Tconv cells marked by expression of (C-C motif) receptor 8 (CCR8) and enriched in Treg-associated transcripts. CCR8+ Tconv cells are found in mouse and human tumors. Upon Treg depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, resulting in IL-10 dependent suppression of anti-tumor immunity. Consequently, conditional deletion of Il10 within T cells augments anti-tumor efficacy upon Treg-depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg-targeted therapies. Overall design: Syngeneic B16-F10 melanoma cells were subcutaneously implanted into Foxp3EGFP-DTR mice and ablated Treg cells through administration of DTx. T cells were isolated by FACS and subjected to RNA-Seq analysisENAregulatory T lymphocyte, Thymus-Dependent Lymphocytes, T-cell surface antigen T4/Leu-3, Malignant Neoplasm, T-cell surface antigen T4|Leu-3, Process, Neoplasms, Benign Neoplasm, RNA-seq., function, T-Lymphocyte, Tumor, Malignant, Cell, alpha-beta regulatory T-lymphocyte, L3T4, Benign, T Lymphocyte, T-cell differentiation antigen L3T4, T-Cell, regulatory T-lymphocyte, Ly-4, Neoplasm, Whole Transcriptome Shotgun Sequencing, CD25-positive, Immune Processes, Immune Responses, suppressor T lymphocyte, Malignancy, alpha-beta regulatory T-cell, T-Cells, T-cell surface glycoprotein CD4, Thymus-Dependent, CD4-positive, T, Benign Neoplasms, CD4mut, Lymphocytes, Cancers, regulatory T-cell, suppressor T cell, Thymus-Dependent Lymphocyte, Malignant Neoplasms, Neoplasias, suppressor T-cell, T Cells, Immune Response, Immune, suppressor T-lymphocyte, Treg, Cells, Response, alpha-beta regulatory T lymphocyte, CD4, T Cell, Malignancies, other neoplasm, Immune Process, T Lymphocytes, Thymus Dependent Lymphocytes, Neoplasia, Lymphocyte, Cancer, Tumorsregulatory T lymphocyte, Thymus-Dependent Lymphocytes, T-cell surface antigen T4/Leu-3, Malignant Neoplasm, T-cell surface antigen T4|Leu-3, Process, Neoplasms, Benign Neoplasm, RNA-seq., function, T-Lymphocyte, Tumor, Malignant, Cell, alpha-beta regulatory T-lymphocyte, L3T4, Benign, T Lymphocyte, T-cell differentiation antigen L3T4, T-Cell, regulatory T-lymphocyte, Ly-4, Neoplasm, Whole Transcriptome Shotgun Sequencing, CD25-positive, Immune Processes, Immune Responses, suppressor T lymphocyte, Malignancy, alpha-beta regulatory T-cell, T-Cells, T-cell surface glycoprotein CD4, Thymus-Dependent, CD4-positive, T, Benign Neoplasms, CD4mut, Lymphocytes, Cancers, regulatory T-cell, suppressor T cell, Thymus-Dependent Lymphocyte, Malignant Neoplasms, Neoplasias, suppressor T-cell, T Cells, Immune Response, Immune, suppressor T-lymphocyte, Treg, Cells, Response, alpha-beta regulatory T lymphocyte, CD4, T Cell, Malignancies, other neoplasm, Immune Process, T Lymphocytes, Thymus Dependent Lymphocytes, Neoplasia, Lymphocyte, Cancer, TumorsfalseAcquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion [RNA-seq II]Acquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion [RNA-seq II]2025-09-242024-01-15PRJNA994054GSE2371401009038100544