# Overcoming obesity-associated immunotherapy resistance in renal cancer

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $551,148

## Abstract

SUMMARY: Our understanding of the mechanisms used by the host immune system to fight growing tumors
has increased exponentially in recent decades, ushering in the development of new therapeutic approaches
such as immune checkpoint blockade (ICB) that have revolutionized cancer treatment. Despite these
advances, many patients fail to respond to even the most promising immunotherapies. Thus, there persists an
urgent need to identify the host factors responsible for the limited efficacy of these otherwise potent
immunotherapies in cancer patients. Not surprisingly, identifying mechanisms of immunotherapy resistance is
an active area of research. However, the vast majority of pre-clinical and clinical studies in this area do not
take into account the effects of common patient co-morbidities like obesity. This is notable because it is
estimated that by 2050 half of all adults in the U.S. will have obesity (defined as a Body Mass Index (BMI)
of >30 kg/m2). Studies focused on understanding the impact of obesity on anti-tumor immunity and cancer
immunotherapy outcomes have grown dramatically in number. However, the field still lacks a clear
understanding of when obesity is beneficial for cancer patients, when it is not, and why. Renal cancer is
one of 13 tumor types whose prevalence is increased by obesity. Multiple independent studies have found that
even in advanced renal cancer patients, 50-60% display BMI-defined overweight or obesity at ICB treatment
initiation. Thus, identifying the biological drivers of obesity-associated ICB resistance versus susceptibility in
renal cancer is a critically important area of research that could directly impact the majority of patients battling
this disease. We have been studying ICB resistance in the context of host obesity. We retrospectively
examined outcomes in a cohort of renal cancer patients who received standard of care anti-PD-1. In patients
with BMI-defined obesity at treatment initiation, 67% exhibited cancer progression at 12 months, whereas the
remaining 33% were progression-free, illustrating the highly variable effects of host obesity on patient
outcomes. This trend was reflected in our pre-clinical model of orthotopic renal cancer, in which we found that
host obesity is linked to cancer progression in 56% of mice that received an anti-PD-1-based combinatorial
immunotherapy. Here we will combine pre-clinical murine and prospective human subject studies to test the
hypothesis that sustained high levels of IL-1b inflammation during ICB therapy are associated with poor
outcomes in renal cancer patients who have obesity. We further predict that blockade of intratumoral IL-1b will
result in a favorable remodeling of the renal TME and improve ICB outcomes. Our findings will permit a
more nuanced understanding of the obesity-associated mediators of ICB resistance in renal cancer
patients, thereby: 1) providing new metrics to use for identifying patients who are less likely to respond to ICB
and 2) facilitati...

## Key facts

- **NIH application ID:** 10583950
- **Project number:** 1R01CA269568-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Lyse A Norian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $551,148
- **Award type:** 1
- **Project period:** 2023-04-03 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10583950

## Citation

> US National Institutes of Health, RePORTER application 10583950, Overcoming obesity-associated immunotherapy resistance in renal cancer (1R01CA269568-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10583950. Licensed CC0.

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