{"doi":"10.1136/jitc-2024-010170","title":"Depletion of conventional CD4<sup>+</sup> T cells is required for robust priming and dissemination of tumor antigen-specific CD8<sup>+</sup> T cells in the setting of anti-CD4 therapy","abstract":"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.","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":443628,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1136599,"name":"Christo Philip C. Dragnev","orcid":"0009-0003-7877-8058","position":1,"is_corresponding":false},{"id":242855,"name":"Tyler G. Searles","orcid":"0000-0003-3146-4812","position":2,"is_corresponding":false},{"id":851556,"name":"Nathaniel Spicer","orcid":"0000-0002-9106-1049","position":3,"is_corresponding":false},{"id":615212,"name":"Tiffany Chen","orcid":"0000-0003-2546-2941","position":4,"is_corresponding":false},{"id":235908,"name":"J. Louise Lines","orcid":"0000-0002-3766-8376","position":5,"is_corresponding":false},{"id":1258829,"name":"Aaron R Hawkes","orcid":null,"position":6,"is_corresponding":false},{"id":1258830,"name":"Wilson L. Davis","orcid":null,"position":7,"is_corresponding":false},{"id":572156,"name":"Asmaa Mohamed","orcid":"0000-0002-8717-2416","position":8,"is_corresponding":false},{"id":626344,"name":"Keisuke Shirai","orcid":"0000-0002-1403-8128","position":9,"is_corresponding":false},{"id":387883,"name":"Joseph D. Phillips","orcid":"0000-0001-9309-7726","position":10,"is_corresponding":false},{"id":266261,"name":"Pamela C. Rosato","orcid":"0000-0001-7909-3868","position":11,"is_corresponding":false},{"id":292415,"name":"Yina H. Huang","orcid":"0000-0002-0125-9351","position":12,"is_corresponding":false},{"id":242856,"name":"Mary Jo Turk","orcid":"0000-0002-9612-8329","position":13,"is_corresponding":false},{"id":1053673,"name":"Delaney E Ramirez","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:01:29.001453Z","pmid":"39521617","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}