34
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade

      research-article
      1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 2 , 3 , 4 , 5 , 4 , 5 , 5 , 6 , 7 , 1 , 8 , 9 , 10 , 1 , 11 , 12 , 1 , 11 , 13 , 14 , 14 , 14 , 15 , 15 , 16 , 17 , 18 , 1 , 13 , # , 19
      Nature medicine

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The recent successes of immunotherapy have shifted the paradigm in cancer treatment but since only a percentage of patients respond, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general, and in cancer immunotherapy, in particular, is poorly understood. Here we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. Strikingly however, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival following checkpoint blockade which directly targets some of the pathways activated in obesity.

          Related collections

          Most cited references27

          • Record: found
          • Abstract: found
          • Article: not found

          Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.

          Nutritional deprivation suppresses immune function. The cloning of the obese gene and identification of its protein product leptin has provided fundamental insight into the hypothalamic regulation of body weight. Circulating levels of this adipocyte-derived hormone are proportional to fat mass but maybe lowered rapidly by fasting or increased by inflammatory mediators. The impaired T-cell immunity of mice now known to be defective in leptin (ob/ob) or its receptor (db/db), has never been explained. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases. We report here that leptin has a specific effect on T-lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Leptin increased Th1 and suppressed Th2 cytokine production. Administration of leptin to mice reversed the immunosuppressive effects of acute starvation. Our findings suggest a new role for leptin in linking nutritional status to cognate cellular immune function, and provide a molecular mechanism to account for the immune dysfunction observed in starvation.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The medical care costs of obesity: an instrumental variables approach.

            This paper is the first to use the method of instrumental variables (IV) to estimate the impact of obesity on medical costs in order to address the endogeneity of weight and to reduce the bias from reporting error in weight. Models are estimated using restricted-use data from the Medical Expenditure Panel Survey for 2000-2005. The IV model, which exploits genetic variation in weight as a natural experiment, yields estimates of the impact of obesity on medical costs that are considerably higher than the estimates reported in the previous literature. For example, obesity is associated with $656 higher annual medical care costs, but the IV results indicate that obesity raises annual medical costs by $2741 (in 2005 dollars). These results imply that the previous literature has underestimated the medical costs of obesity, resulting in underestimates of the economic rationale for government intervention to reduce obesity-related externalities. Copyright © 2011 Elsevier B.V. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Obesity, Inflammation, and Cancer.

              Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including cancer, and is increasingly recognized as a growing cause of preventable cancer risk. Chronic inflammation, a well-known mediator of cancer, is a central characteristic of obesity, leading to many of its complications, and obesity-induced inflammation confers additional cancer risk beyond obesity itself. Multiple mechanisms facilitate this strong association between cancer and obesity. Adipose tissue is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of proinflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance protumoral effects. Dysregulated metabolism that stems from obesity, including insulin resistance, hyperglycemia, and dyslipidemia, can further impact tumor growth and development. This review describes how adipose tissue becomes inflamed in obesity, summarizes ways these mechanisms impact cancer development, and discusses their role in four adipose-associated cancers that demonstrate elevated incidence or mortality in obesity.
                Bookmark

                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                17 September 2018
                12 November 2018
                January 2019
                12 May 2019
                : 25
                : 1
                : 141-151
                Affiliations
                [1 ]Department of Dermatology, UC Davis School of Medicine, Sacramento, California, 95816, USA
                [2 ]Department of Surgical and Radiological Sciences, School of Veterinary Medicine, UC Davis, Davis, California 95616, USA
                [3 ]Division of Experimental Medicine, UC San Francisco, San Francisco, California 94110, USA
                [4 ]Department of Medical Microbiology and Immunology, UC Davis, Davis, California 95616, USA
                [5 ]California National Primate Research Center, UC Davis, Davis, California 95616, USA
                [6 ]Department of Pediatrics, UC Davis School of Medicine, Davis, California 95616, USA
                [7 ]Department of Cell Biology and Human Anatomy, UC Davis, Davis, California 95616, USA
                [8 ]Dermatology Service, Sacramento VA Medical Center, Mather, California 95655, USA
                [9 ]Department of Urology, Center for Immunology, Masonic Cancer Center, Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, Minnesota 55455, USA
                [10 ]Department of Pathology & Translational Immuno-oncology Laboratory, Yale University School of Medicine, New Haven, Connecticut 06510, USA
                [11 ]Immune Monitoring Core, UC Davis Comprehensive Cancer Center, Sacramento, California 95817, USA
                [12 ]Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA
                [13 ]Department of Internal Medicine, Division of Hematology and Oncology, UC Davis School of Medicine, Sacramento, California 95817, USA
                [14 ]Department of Internal Medicine, Section of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
                [15 ]Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
                [16 ]Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA
                [17 ]Masonic Cancer Center and Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA
                [18 ]Division of Surgical Oncology, Department of Surgery, UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, California 95817, USA
                [19 ]Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, UC School of Medicine, Sacramento, California 95817, USA
                Author notes

                Author Contributions

                Murine studies: Z.W., E.G.A., J.I.L., A.M., C.T.L., L.T.K., C.D., C.M.M., K.M.S., I.R.S., S.K.G., A.S., A.M.M.

                Murine studies data analysis / interpretation: Z.W., E.G.A., J.I.L., A.M., C.T.L., L.T.K., C.D., C.M.M., K.M.S., I.R.S., T.S.G., D.L.L., B.R.B., R.J.C., W.J.M., A.M.M.

                Primate Studies: D.J.H.-O., G.M.-L., A.F.T.

                Human blood donor studies: Z.W., A.M.M., K.K.

                Human Multiplex IF: K.A.S.

                TCGA analysis: A.M., E.M.

                Clinical study: R.A., S.I., S.M., M.M., S.K.V.

                Overall Study Conception: W.J.M.

                Overall Study Design: W.J.M., A.M.M.

                Overall Study Supervision: W.J.M., A.M.M.

                Manuscript preparation: Z.W., E.G.A., R.J.C., W.J.M, A.M.M.

                Manuscript critical review: Z.W., E.G.A., J.I.L., A.M., C.T.L., L.T.K., C.D., C.M.M., K.M.S., I.R.S., S.K.G., S.S.W., R.B.R., D.J.H.-O., G.M.-L., A.F.T., R.R.I., T.S.G., K.A.S., A.M., E.M., R.A., S.I., S.M., M.M., S.K.V., D.L.L., B.R.B., R.C., K.K.

                [# ]Corresponding Author: Dr. William J. Murphy, Distinguished Professor, Departments of Dermatology and Internal Medicine, UC Davis School of Medicine, University of California, Davis, 2921 Stockton Blvd, IRC Bldg, Rm.1614. Sacramento, CA 95817, Tel.: 916-703-9397 Fax: 916-703-9396, wmjmurphy@ 123456ucdavis.edu
                Article
                NIHMS1506652
                10.1038/s41591-018-0221-5
                6324991
                30420753
                c9754d23-e9f5-403f-82cc-571ac9ed8bea

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Medicine
                Medicine

                Comments

                Comment on this article