{"doi":"10.21203/rs.2.15818/v2","title":"The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer","abstract":"Abstract Background: Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. Results: In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine’s versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6J E0771 murine breast cancer model. Conclusions: Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.","journal":"Research Square","year":2020,"id":128390,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":404268,"name":"Laura Graham","orcid":"0000-0002-7093-9748","position":1,"is_corresponding":false},{"id":579025,"name":"Timothy Smith","orcid":null,"position":2,"is_corresponding":false},{"id":578738,"name":"Carmen Camarena","orcid":"0000-0002-7030-171X","position":3,"is_corresponding":false},{"id":417221,"name":"Matthew Zellner","orcid":null,"position":4,"is_corresponding":false},{"id":579026,"name":"Jamie-Jean S Gilmer","orcid":null,"position":5,"is_corresponding":false},{"id":463745,"name":"Sheela Damle","orcid":"0000-0001-6688-0950","position":6,"is_corresponding":false},{"id":416520,"name":"Daniel H. Conrad","orcid":"0000-0002-4791-2694","position":7,"is_corresponding":false},{"id":274831,"name":"Rebecca Martin","orcid":"0000-0001-9948-5463","position":8,"is_corresponding":false},{"id":232395,"name":"Harry D. Bear","orcid":"0000-0002-7632-9019","position":9,"is_corresponding":false},{"id":463744,"name":"Andrea Luker","orcid":"0000-0003-3131-8049","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-18T23:15:38.879956Z","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":[]}