Abstract B15: The effects of obesity on tumor microenvironment and immunotherapy efficacy
Authors: Dudzinski Stephanie O. , Beckermann Kathryn E. , Giorgio Todd D. , Rathmell Jeffrey C. 
Published: May 2018

Abstract
Immunotherapy is a promising treatment for cancer. Although immune checkpoint blockade treatment is life-saving for some patients, only a minority respond to it. There are no clear data from clinical trials to suggest what risk factors that are common among patients affect immunotherapy treatment efficacy. For example, obesity is a risk factor for at least thirteen different types of cancer, including colon and breast, and one-third of Americans are obese. However, no conclusive studies examining the efficacy of cancer immunotherapies in obese patients have been performed. Furthermore, while many cancer patients are obese, preclinical models of immunotherapy typically use lean mice. Studies have shown that obesity promotes a vastly different immune system compared to a lean state. Obesity promotes an increase in adipose tissue macrophages, which tend to have a proinflammatory “M1” polarization, whereas tumor-associated macrophages (TAMs) have an antiinflammatory “M2” polarization. M1 macrophages create a proinflammatory tumor microenvironment, which is potentially favorable for immunotherapy. However, the characteristics of TAMs in obese subjects are poorly described. One theory is that in obesity, the tumor microenvironment shifts the macrophages from the M1 phenotype towards the TAM M2 phenotype, which would result in a worse response to immune checkpoint blockade. Also, obese individuals have a decreased humoral immune response due to a multitude of factors, including an altered lymphocyte profile, decreased lymphocyte functionality, dysregulated cytokines, and decreased numbers of immune cells, which would also worsen treatment response. A second theory is that obese individuals often have a higher mutational load in their tumors, as is seen in increased genomic instability in obese patients with colon cancer and endometrial cancer. Higher mutational loads correlate with immunogenic tumors and often better responses to immunotherapy treatment. It is not clear how these immunologic and genetic differences in obesity will affect response to immunomodulatory therapies. Therefore, our first goal is to understand obesity's immunologic effects on immunotherapy efficacy. We studied the effects of obesity on the tumor microenvironment using a diet-induced obesity mouse model and immunoresponsive cell line. MC38 colon cancer cells were injected subcutaneously in C57BL/6 mice fed a high-fat or control diet. The tumors were collected three weeks post-injection and processed into single cell suspensions for flow cytometry. Samples were stained for helper T cells, cytotoxic T cells, and macrophages with CD11b and F4/80, where CD206 and CD86 identified M2 and M1 macrophages, respectively. Initial experiments revealed a higher concentration of CD4+ T cells in lean mice. We will further investigate the role of immune cell and cytokine differences in obese states. However, when anti-PD-1 antibodies were intraperitoneally administered to the mice on day 7, 10, and 13 post-MC38 cell injection, the high-fat diet mice tumors had higher concentrations of CD4+ T cells compared to low-fat diet mice tumors. These experiments are being repeated, and we are now using an orthotopic EMT6 breast cancer model as well. The importance of identifying optimal diet-induced obese mouse models that are compatible with immunoresponsive cell lines is imperative to conducting translational research and is a focal objective of the ongoing studies. In later experiments, we have engineered biocompatible nanoparticles that can modulate immune cells and shift the tumor microenvironment using siRNA, potentially improving immunotherapy efficacy in obesity. The nanoparticles will identify the role of macrophages in immunotherapy efficacy. These initial studies will lay the foundation for future research and have important translational implications in improving the efficacy of immunotherapy treatment in obese patients.
Citation Format: Stephanie O. Dudzinski, Kathryn E. Beckermann, Todd D. Giorgio, Jeffrey C. Rathmell. The effects of obesity on tumor microenvironment and immunotherapy efficacy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B15.