Dietary β-Hydroxy-β-Methylbutyrate Supplementation Promotes PDAC Response to Gemcitabine and Immunotherapy Response in Obese Mice

Document Type

Article

Publication Date

6-2020

Department

Department of Biological Sciences

Abstract

Objectives

Late diagnosis, aggressive underlying biology, and limited treatment options contribute towards the exceptionally poor survival of pancreatic ductal adenocarcinoma (PDAC). Obesity promotes both incidence and progression of PDAC via chronic systemic inflammation, generation of an immunosuppressive tumor microenvironment, and promotion of tumor fibrosis. β-Hydroxy-β-Methylbutyrate (HMB) reduces cancer associated cachexia and promotes modest reductions in tumor growth in animal models of cancer. The objective of this study was to determine if HMB supplementation would alter therapeutic response to either gemcitabine or anti-PD1 immunotherapy. Methods

C57BL/6 mice were fed either a diet induced obesity high fat diet or a matched low fat control. Following PANC02 tumor induction, animals were treated with HMB alone or in combination with gemcitabine or anti-PD1 immunotherapy. Tumor transcriptomic analysis was preformed using Affymetrix microarray, with subsequent gene set enrichment analysis. Immunohistochemistry was performed for CD3 (a T cell marker). C57BL/6 mice were fed either a diet induced obesity high fat diet or a matched low fat control. Following PANC02 tumor induction, animals were treated with HMB alone or in combination with gemcitabine or anti-PD1 immunotherapy. Tumor transcriptomic analysis was preformed using Affymetrix microarray, with subsequent gene set enrichment analysis. Immunohistochemistry was performed for CD3 (a T cell marker). Results

DIO-induced immune suppression was partially reversed by HMB, with reduced tumor growth, increased T cell markers and enhanced efficacy of gemcitabine following HMB treatment in obese mice. Separately, HMB enhanced the efficacy of anti-PD1 immunotherapy. Conclusions

HMB enhanced PDAC immune surveillance, augmenting both cytotoxic chemotherapy and immunotherapy. HMB-induced suppression of obesity driven PDAC tumor growth, and promotion of immune surveillance may provide extend the therapeutic index of both chemotherapies and immunotherapies in PDAC.

Publisher's Statement

Copyright ©2020 The Author(s) on behalf of the American Society for Nutrition 2020. Publisher’s version of record: https://doi.org/10.1093/cdn/nzaa044_012

Publication Title

Current Developments in Nutrition

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