# The Effects of Obesity on the Efficacy of Immunotherapy

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2020 · $42,080

## Abstract

PROJECT SUMMARY
Immunotherapy treatments can be life saving for cancer patients, but only a small fraction of patients respond to
this therapy. There have been no studies to date describing the characteristics of patients that respond compared
to non-responders. Obesity and advanced age are important cancer risk factors, and both of these factors
contribute to substantial immune dysfunction in patients. In obesity, there are more adipose tissue macrophages
than in lean individuals, and these macrophages are of a pro-inflammatory “M1” phenotype, whereas most lean
individuals have pre-dominantly “M2” anti-inflammatory macrophages. However, the change in macrophage
polarization from an adipose tissue microenvironment to a tumor microenvironment is poorly described.
Understanding if the tumor associated macrophages in obesity maintain their “M1” phenotype or change to a
tumor association macrophage “M2” phenotype is critical in hypothesizing if obese patients will respond more or
less effectively to immunotherapy. Additionally, many tumors in obese patients have higher mutational loads due
to increased cellular reactive oxygen species, such as higher rates of genomic instability in colon cancer and
endometrial cancer. Higher mutational loads are a prognostic factor positively correlated with immunotherapy
efficacy, since the tumors are more immunogenic. Given these opposing obesity-induced changes, correlation
of immunotherapy efficacy and obesity is unpredictable. The overall goal of this proposal is to understand how
the systemic and tumor immune microenvironment differences in obesity affect immunotherapy efficacy and to
determine the role of tumor associated macrophages in immunotherapy efficacy. We have established a diet-
induced obesity mouse model using a 60% kcal high-fat diet in C57BL/6 mice that is compatible with the MC38
colon cancer cell line, which is well-published as an immunoresponsive cell line to immune checkpoint blockade
treatments. In Specific Aim 1, we will investigate how systemic and tumor immune microenvironment
differences in obese and lean mice affect anti-PD-1 treatment efficacy and the systemic and tumor immune
microenvironment post-treatment. In Specific Aim 2, we will determine the role of tumor associated
macrophages in anti-PD-1 treatment efficacy by treating mice with a mannosylated delivery system for IκBa
siRNA, which activates the NFκB pathway and creates pro-inflammatory, M1 macrophages. For both of these
aims we will characterize the tumor immune microenvironments using flow cytometry and immunohistochemistry,
while systemic cytokines and adipokines will be analyzed using ELISA and Luminex assays. Together, these
studies will define the role of obesity and tumor associated macrophages in immune checkpoint blockade efficacy
and will suggest if translational mouse models should include obese murine studies before new immunotherapy
drugs are used clinically. Further, these results will identify methods in which t...

## Key facts

- **NIH application ID:** 9834842
- **Project number:** 5F30CA224559-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Stephanie Dudzinski
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,080
- **Award type:** 5
- **Project period:** 2018-02-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834842

## Citation

> US National Institutes of Health, RePORTER application 9834842, The Effects of Obesity on the Efficacy of Immunotherapy (5F30CA224559-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9834842. Licensed CC0.

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