{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:03:27Z","timestamp":1789664607179,"version":"4.0.1"},"reference-count":47,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R35 CA197627"],"award-info":[{"award-number":["R35 CA197627"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, and effective therapies for PDAC are currently lacking. Moreover, PDAC is promoted and exacerbated by obesity, while cachexia and sarcopenia are exceptionally common comorbidities that predict both poor survival and treatment response. Managing PDAC with immunotherapies has thus far proven ineffective, partly due to the metabolically hostile tumor microenvironment. \u03b2-hydroxy-\u03b2-methylbutyrate (HMB), a metabolite of leucine commonly used as a dietary supplement to boost muscle growth and immune function, may be an attractive candidate to augment PDAC therapy. We therefore sought to test the hypothesis that HMB would enhance antitumor immunity while protecting mouse muscle mass. Control and diet-induced obese C57BL\/6 male mice bearing subcutaneously injected Panc02 tumors were supplemented with 1% HMB and treated with or without 50 mg\/kg gemcitabine (n = 15\/group). HMB was associated with reduced muscle inflammation and increased muscle fiber size. HMB also reduced tumor growth and promoted antitumor immunity in obese, but not lean, mice, independent of the gemcitabine treatment. Separately, in lean tumor-bearing mice, HMB supplementation promoted an anti-PD1 immunotherapy response (n = 15\/group). Digital cytometry implicated the decreased abundance of M2-like macrophages in PDAC tumors, an effect that was enhanced by anti-PD1 immunotherapy. We confirmed that HMB augments M1-like macrophage (antitumor) polarization. These preclinical findings suggest that HMB has muscle-sparing and antitumor activities against PDAC in the context of obesity, and that it may sensitize otherwise nonresponsive PDAC to immunotherapy.<\/jats:p>","DOI":"10.3390\/cancers13246359","type":"journal-article","created":{"date-parts":[[2021,12,19]],"date-time":"2021-12-19T20:41:55Z","timestamp":1639946515000},"page":"6359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["\u03b2-Hydroxy-\u03b2-Methylbutyrate Supplementation Promotes Antitumor Immunity in an Obesity Responsive Mouse Model of Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6914-848X","authenticated-orcid":false,"given":"Michael F.","family":"Coleman","sequence":"first","affiliation":[{"name":"Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristyn A.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Texas, Austin, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Pfeil","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhas K.","family":"Etigunta","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Michigan Technical University, Houghton, MI 49931, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Fabela","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Lashinger","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Texas, Austin, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengrong","family":"Cui","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Texas, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Hursting","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.3748\/wjg.v24.i20.2137","article-title":"Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?","volume":"24","author":"Hilmi","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e55185","DOI":"10.7554\/eLife.55185","article-title":"The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy","volume":"9","author":"Lim","year":"2020","journal-title":"eLife"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Coleman, M.F., Cozzo, A.J., Pfeil, A.J., Etigunta, S.K., and Hursting, S.D. (2020). Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy. Cancers, 12.","DOI":"10.3390\/cancers12040852"},{"key":"ref_4","first-page":"9361","article-title":"Cachexia and pancreatic cancer: Are there treatment options?","volume":"20","author":"Mueller","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"601434","DOI":"10.1155\/2011\/601434","article-title":"Cancer cachexia: Mechanisms and clinical implications","volume":"2011","author":"Donohoe","year":"2011","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5841","DOI":"10.1158\/1078-0432.CCR-18-0415","article-title":"Pembrolizumab Exposure\u2013Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance","volume":"24","author":"Turner","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.coi.2018.03.012","article-title":"Obesity induced T cell dysfunction and implications for cancer immunotherapy","volume":"51","author":"Aguilar","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_8","unstructured":"WCRF\/AICR (2018). Diet, Nutrition, Physical Activity and Cancer: A Global Perspective, WCRF. Continuous Update Project Expert Report."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"999","DOI":"10.3945\/ajcn.113.071399","article-title":"Obesity paradox in cancer: New insights provided by body composition","volume":"99","author":"Gonzalez","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6973","DOI":"10.1158\/1078-0432.CCR-09-1525","article-title":"Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer","volume":"15","author":"Tan","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1158\/1940-6207.CAPR-11-0023","article-title":"Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer","volume":"4","author":"Lashinger","year":"2011","journal-title":"Cancer Prev. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"834294","DOI":"10.1155\/2014\/834294","article-title":"Quercetin protects against obesity-induced skeletal muscle inflammation and atrophy","volume":"2014","author":"Le","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9562","DOI":"10.1200\/JCO.2019.37.15_suppl.9562","article-title":"The relationship between obesity and immunotherapy: It\u2019s complicated","volume":"37","author":"Donnelly","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41591-018-0221-5","article-title":"Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade","volume":"25","author":"Wang","year":"2018","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s40425-019-0527-y","article-title":"A multicenter study of body mass index in cancer patients treated with anti-PD-1\/PD-L1 immune checkpoint inhibitors: When overweight becomes favorable","volume":"7","author":"Cortellini","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/S1470-2045(18)30078-0","article-title":"Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: A retrospective, multicohort analysis","volume":"19","author":"McQuade","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1084\/jem.20140116","article-title":"Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice","volume":"211","author":"Mirsoian","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.2174\/18715206113139990321","article-title":"\u03b2-Hydroxy-\u03b2-methylbutyrate as a countermeasure for cancer cachexia: A cellular and molecular rationale","volume":"13","author":"Kim","year":"2013","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1550-2783-10-6","article-title":"International Society of Sports Nutrition Position Stand: \u03b2-Hydroxy-\u03b2-methylbutyrate (HMB)","volume":"10","author":"Wilson","year":"2013","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.nutres.2008.04.006","article-title":"\u03b2-Hydroxy-\u03b2-methylbutyrate supplementation reduces tumor growth and tumor cell proliferation ex vivo and prevents cachexia in Walker 256 tumor-bearing rats by modifying nuclear factor-\u03baB expression","volume":"28","author":"Nunes","year":"2008","journal-title":"Nutr. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0165-2427(98)00211-6","article-title":"In vitro exposure with \u03b2-Hydroxy-\u03b2-methylbutyrate enhances chicken macrophage growth and function","volume":"67","author":"Peterson","year":"1999","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"W\u00f3jcik, R., Z\u0105bek, K., Ma\u0142aczewska, J., Milewski, S., and Kaczorek-\u0141ukowska, E. (2019). The Effects of \u03b2-Hydroxy-\u03b2-Methylbutyrate (HMB) on Chemotaxis, Phagocytosis, and Oxidative Burst of Peripheral Blood Granulocytes and Monocytes in Goats. Animals, 9.","DOI":"10.3390\/ani9121031"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.3389\/fimmu.2019.01818","article-title":"The TNF Paradox in Cancer Progression and Immunotherapy","volume":"10","author":"Montfort","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"843","DOI":"10.3892\/or.2010.843","article-title":"Anti-tumor effect by inhibition of NF-\u03baB activation using nafamostat mesilate for pancreatic cancer in a mouse model","volume":"24","author":"Furukawa","year":"2010","journal-title":"Oncol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1681\/ASN.2006010083","article-title":"Protein degradation by the ubiquitin\u2013proteasome pathway in normal and disease states","volume":"17","author":"Lecker","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.ajpath.2010.12.009","article-title":"NF-\u03baB inhibition protects against tumor-induced cardiac atrophy in vivo","volume":"178","author":"Wysong","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1016\/j.metabol.2013.06.005","article-title":"HMB attenuates muscle loss during sustained energy deficit induced by calorie restriction and endurance exercise","volume":"62","author":"Park","year":"2013","journal-title":"Metabolism"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/nm.3221","article-title":"Inflammasome-derived IL-1\u03b2 production induces nitric oxide-mediated resistance to Leishmania","volume":"19","author":"Costa","year":"2013","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.3389\/fimmu.2018.01286","article-title":"seq-ImmuCC: Cell-Centric View of Tissue Transcriptome Measuring Cellular Compositions of Immune Microenvironment from Mouse RNA-Seq Data","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"748","DOI":"10.12688\/f1000research.11622.1","article-title":"CyTOF workflow: Differential discovery in high-throughput high-dimensional cytometry datasets","volume":"6","author":"Nowicka","year":"2017","journal-title":"F1000Research"},{"key":"ref_34","unstructured":"Sorenson, R.L., and Brelje, T.C. (2014). Atlas of Human Histology: A Guide to Microscopic Structure of Cells, Tissues and Organs, University of Minnesota. [3rd ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.nmd.2004.06.008","article-title":"Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse","volume":"14","author":"Briguet","year":"2004","journal-title":"Neuromuscul. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00726-015-2067-1","article-title":"The role of leucine and its metabolites in protein and energy metabolism","volume":"48","author":"Duan","year":"2016","journal-title":"Amino Acids"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41596-018-0103-9","article-title":"Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap","volume":"14","author":"Reimand","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12943-020-01151-3","article-title":"Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma","volume":"19","author":"Fan","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1126\/science.289.5488.2363","article-title":"NF-\u03baB-induced loss of MyoD messenger RNA: Possible role in muscle decay and cachexia","volume":"289","author":"Guttridge","year":"2000","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1002\/jcsm.12208","article-title":"\u03b2-Hydoxy-\u03b2-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions","volume":"8","author":"Holecek","year":"2017","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Nishioka, N., Uchino, J., Hirai, S., Katayama, Y., Yoshimura, A., Okura, N., Tanimura, K., Harita, S., Imabayashi, T., and Chihara, Y. (2019). Association of Sarcopenia with and Efficacy of Anti-PD-1\/PD-L1 Therapy in Non-Small-Cell Lung Cancer. J. Clin. Med., 8.","DOI":"10.3390\/jcm8040450"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1038\/s41598-019-39120-6","article-title":"Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study","volume":"9","author":"Shiroyama","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1749-6632.2011.06096.x","article-title":"The growing challenge of obesity and cancer: An inflammatory issue","volume":"1229","author":"Harvey","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/2049-3002-2-6","article-title":"Leucine supplementation differentially enhances pancreatic cancer growth in lean and overweight mice","volume":"2","author":"Liu","year":"2014","journal-title":"Cancer Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.cmet.2019.06.001","article-title":"Macrophages and Metabolism in the Tumor Microenvironment","volume":"30","author":"Vitale","year":"2019","journal-title":"Cell Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.clnu.2006.05.007","article-title":"\u03b2-Hydoxy-\u03b2-methylbutyrate supplementation affects Walker 256 tumor-bearing rats in a time-dependent manner","volume":"26","author":"Caperuto","year":"2007","journal-title":"Clin. Nutr."},{"key":"ref_47","first-page":"713","article-title":"\u03b2-Hydroxy-\u03b2-methylbutyrate (HMB) attenuates muscle and body weight loss in experimental cancer cachexia","volume":"38","author":"Aversa","year":"2011","journal-title":"Int. J. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/24\/6359\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:51:23Z","timestamp":1760169083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/24\/6359"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,18]]},"references-count":47,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cancers13246359"],"URL":"https:\/\/doi.org\/10.3390\/cancers13246359","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,18]]}}}