ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/071/SRR25204271/SRR25204271_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/069/SRR25204269/SRR25204269_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/073/SRR25204273/SRR25204273_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/069/SRR25204269/SRR25204269_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/075/SRR25204275/SRR25204275_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/072/SRR25204272/SRR25204272_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/071/SRR25204271/SRR25204271_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/074/SRR25204274/SRR25204274_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/068/SRR25204268/SRR25204268_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/070/SRR25204270/SRR25204270_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/072/SRR25204272/SRR25204272_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/074/SRR25204274/SRR25204274_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/068/SRR25204268/SRR25204268_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/073/SRR25204273/SRR25204273_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/070/SRR25204270/SRR25204270_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR252/075/SRR25204275/SRR25204275_1.fastq.gzprimaryOK200GenomicsRoychoudhuri Laboratory, Department of Pathology, University of Cambridgehttps://www.ebi.ac.uk/ena/browser/view/PRJNA992496Mus 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 analysisENAfalseAcquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion [RNA-seq]Acquisition of suppressive function by CD4+ conventional T cells limits anti-tumor immunity driven by Treg depletion [RNA-seq]2025-09-242024-01-15PRJNA992496GSE2368231009038100544