{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T20:41:05Z","timestamp":1792874465448,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,3,27]],"date-time":"2020-03-27T00:00:00Z","timestamp":1585267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-14-1-0576"],"award-info":[{"award-number":["W81XWH-14-1-0576"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["KL2 TR002530 and UL1 TR002529"],"award-info":[{"award-number":["KL2 TR002530 and UL1 TR002529"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007544","name":"Boler Family Foundation","doi-asserted-by":"publisher","award":["Research support"],"award-info":[{"award-number":["Research support"]}],"id":[{"id":"10.13039\/100007544","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008109","name":"University of Notre Dame","doi-asserted-by":"publisher","award":["Integrated Biomedical Sciences Graduate Program"],"award-info":[{"award-number":["Integrated Biomedical Sciences Graduate Program"]}],"id":[{"id":"10.13039\/100008109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Granulocytic myeloid-derived suppressor cells (Gr-MDSCs) promote immune evasion and resistance to immunotherapeutics in a variety of malignancies. Our previous study showed that dual PI3K\/mTOR inhibitor Dactolisib impaired the viability and immunosuppressive function of Gr-MDSCs, and significantly synergized with immune checkpoint blockade (ICB) antibodies targeting PD1 and CTLA4 to eradicate metastatic castration-resistant prostate cancer (CRPC) in a preclinical transgenic mouse model. On the contrary, tyrosine kinase inhibitor Dasatinib diminished tumor-infiltrating T lymphocytes and showed no synergic activity with ICB. The understanding of the distinct effects of Dactolisib and Dasatinib on Gr-MDSCs, T cells and prostate neoplastic cells is inadequate, limiting the clinical translation of the combination immunotherapy. To address this question, we applied Reverse Phase Protein Array (RPPA) to profile 297 proteins and protein phosphorylation sites of Gr-MDSCs, T cells and prostate cancer cells isolated from the CRPC model. We found cell type-specific protein expression patterns and highly selective targets by the two drugs, including preferential inhibition of phospho-4E-BP1 in Gr-MDSCs by Dactolisib and preferential suppression of phospho-Src and phospho-p38 MAPK in T cells. Furthermore, transcriptomic profiling of Gr-MDSCs treated with the two inhibitors revealed downregulation of mitochondrial respiration pathways by Dactolisib but not Dasatinib. Overall, these results provide important mechanistic insight into the efficacious combination of Dactolisib and ICB as well as the detrimental effect of Dasatinib on anti-tumor immunity.<\/jats:p>","DOI":"10.3390\/ijms21072337","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T03:44:13Z","timestamp":1585712653000},"page":"2337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Differential Targeting of Gr-MDSCs, T Cells and Prostate Cancer Cells by Dactolisib and Dasatinib"],"prefix":"10.3390","volume":"21","author":[{"given":"Guoqiang","family":"Liu","sequence":"first","affiliation":[{"name":"Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA"},{"name":"Department of Biological Sciences, Boler\u2013Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Boler\u2013Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0284-6478","authenticated-orcid":false,"given":"Xin","family":"Lu","sequence":"additional","affiliation":[{"name":"Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA"},{"name":"Department of Biological Sciences, Boler\u2013Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA"},{"name":"Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nri3175","article-title":"Coordinated regulation of myeloid cells by tumours","volume":"12","author":"Gabrilovich","year":"2012","journal-title":"Nat. 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