{"doi":"10.1101/2021.02.23.432584","title":"Cell Communication Network factor 4 promotes tumor-induced immunosuppression in melanoma","abstract":"ABSTRACT Immune cell composition within the tumor microenvironment is regulated by tumor-derived factors. Cell Communication Network factor 4 (CCN4/WISP1) is a matricellular protein secreted by cancer cells that promotes metastasis by inducing the epithelial-mesenchymal transition. While metastatic dissemination limits patient survival, the absence of anti-tumor immunity also associates with poor patient out-comes with recent work suggesting these two clinical correlates are linked. Motivated by finding that CCN4 was associated with a dampened anti-tumor immune contexture in patients diagnosed with primary melanoma, we tested for a direct causal link by knocking out CCN4 (CCN4-KO) in the B16F0 and YUMM1.7 mouse models for melanoma. Tumor growth was significantly reduced when CCN4-KO melanoma cells were implanted subcutaneously in immunocompetent C57BL/6 mice but not in immunodeficient NSG mice. Correspondingly, the frequency of total CD45 + tumor-infiltrating leukocytes was significantly increased in CCN4-KO tumors, with increased natural killer (NK) and effector CD8 + T cells and reduced myeloid-derived suppressor cells (MDSC). Additionally, the absence of tumor-derived CCN4 was associated with an impaired splenic generation of suppressive granulocytic MDSC. Among mechanisms linked to local immunosuppression, we found CCN4 directly suppressed antigen-induced IFN γ release by CD8 + T cells, promoted glycolysis and consequent lactate release by melanoma cells, and enhanced tumor secretion of MDSC-attracting chemokines like CCL2 and CXCL1. Finally, CCN4-KO in B16F0 and YUMM1.7 melanoma cells complemented the anti-tumor effect of immune checkpoint blockade (ICB) therapy. Overall, our results suggest that CCN4 promotes tumor-induced immunosuppression and is a potential target for therapeutic combinations with ICB. Statement of Significance Given emerging interest in understanding the interplay between functional plasticity and anti-tumor immunity, Cell Communication Network factor 4, a secreted matricellular protein linked to promoting metastasis in melanoma, also suppresses anti-tumor immunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217202,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":18248,"name":"Wentao Deng","orcid":"0000-0001-6501-1737","position":1,"is_corresponding":false},{"id":339761,"name":"Sarah L. McLaughlin","orcid":"0000-0002-8413-3585","position":2,"is_corresponding":false},{"id":574504,"name":"Anika Pirkey","orcid":"0000-0002-5349-3561","position":3,"is_corresponding":false},{"id":441040,"name":"Stephanie L. Rellick","orcid":null,"position":4,"is_corresponding":false},{"id":447452,"name":"David J. Klinke","orcid":"0000-0003-3299-4938","position":5,"is_corresponding":false},{"id":574502,"name":"Audry Fernández","orcid":"0000-0002-3436-625X","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T23:53:15.868165Z","pmid":null,"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":[]}