# Innate Immune Mechanisms Contributing to Cancer Growth in Obesity

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $485,465

## Abstract

Project Summary/Abstract
Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, and obesity, which
affects 40% of the population, not only increases the risk of developing CRC, but also increases CRC mortality
through unknown mechanisms. Our preliminary studies demonstrate that CRC grows faster in mice rendered
obese through a high fat diet (HFD), and that the tumor associated macrophages (TAMs) in these mice exhibit
higher expression of the acid sensing receptor, GPR65, which is known to dampen the immune response.
Moreover, in HFD-induced obese mice lacking GRP65, TAMs secrete more TNF-α and tumor growth is retarded.
Given that TAMs but not normal tissue macrophages of obese mice exhibit increased GPR65, we examined the
pH of the tumors in these mice and found them to be more acidic. On the basis of these findings, we hypothesize
that excess lipids in the HFD alter tumor cell metabolism resulting in increased acid production, which potentiates
GPR65 expression and signaling in TAMs, causing them to become immunosuppressive and promote tumor
growth. To test this hypothesis we will pursue the following specific aims: 1) Determine the contribution of
GPR65 signaling to TAM function and CRC growth under conditions of obesity by determining if the cAMP-
PKA signaling axis, which functions downstream of GPR65, is activated in TAMs of obese mice and controls
TNF-α production. We will also analyze GPR65 expression and the cytokine secretion capacity of macrophages
from healthy blood donors and TAMs in CRC samples from non-obese and obese patients; 2) Identify the
mechanism by which HFD promotes GPR65 signaling in CRC TAMs by testing the ability of HFD and oleic
acid, a dietary triglyceride that is highly enriched in HFD tumors, to alter the oxidative potential, fatty acid
oxidation capacity and acid production of human tumor cells via flow cytometry, CyTOF and Seahorse assays.
We will also determine if a high-oleic-acid diet is sufficient to modify GPR65 expression and cytokine production
by TAMs, and examine if tumor acidity is required for the blunted inflammatory response of TAMs; and verify the
role of GPR65 in human macrophages and 3) Assess the effects of targeting GPR65 for tumor
immunotherapy in obese and nonobese mice with CRC and other tumor types, namely hepatocellular
carcinoma and melanoma, and assess the effects of checkpoint blocking antibodies on tumor growth and anti-
tumor immunity in GPR65+ and GPR-/- mice bearing these tumors. The results of these studies are expected to
not only reveal a critical mechanism responsible for accelerated tumor growth in the setting of obesity, but also
identify a novel target for the treatment of these cancers.

## Key facts

- **NIH application ID:** 10654802
- **Project number:** 5R01CA262361-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** EDGAR G. ENGLEMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $485,465
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10654802

## Citation

> US National Institutes of Health, RePORTER application 10654802, Innate Immune Mechanisms Contributing to Cancer Growth in Obesity (5R01CA262361-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10654802. Licensed CC0.

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