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

Abstract

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, 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, 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. 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 after checkpoint blockade which directly targets some of the pathways activated in obesity.

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Fig. 1: Obesity-related T cell dysfunction across multiple species.
Fig. 2: Obesity promotes tumor growth and T cell exhaustion.
Fig. 3: Leptin level are correlated with PD-1 expression.
Fig. 4: Lack of leptin signaling rescues T cells from exhaustion in obese mice.
Fig. 5: Improved efficacy of αPD-1 treatment in DIO mice.
Fig. 6: Exhaustion profile and improved efficacy of aPD-(L)1 immunotherapy in obese patients with cancer.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The datasets generated during and/or analyzed during the current study are available in the NCBI BioSample repository under accession numbers SAMN09873568 and SAMN09873569.

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Acknowledgements

We would like to thank W. Ma and M. Metcalf from the Murphy lab, D. Rowland, A. Chaudhari and Z. Harmany from the UC Davis CMGI and J. Chen in the UC Davis Pathology Core for their technical expertise and help. We would also like to thank the other members in the Murphy lab for providing feedback and suggestions during preparation of the manuscript. This was work funded by NIH grant R01 CA095572, R01 CA195904, R01 CA214048, P01 CA065493, R01 HL085794, the California National Primate Research Center base operating grant (OD011107), the UC Davis Comprehensive Cancer Center Support Grant (CCSG) (P30 CA093373) and the UC Davis Mouse Metabolic Phenotyping Center (MMPC) grant (DK092993). The content of this publication does not necessarily reflect the view or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, NCI, NHLBI and Center for Cancer Research.

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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’C., 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’C., 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.

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Correspondence to William J. Murphy.

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Wang, Z., Aguilar, E.G., Luna, J.I. et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 25, 141–151 (2019). https://doi.org/10.1038/s41591-018-0221-5

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