# Identifying gut bacterial molecules and mechanisms that promote an anti-tumor response to immunotherapy

> **NIH NIH K22** · HARVARD MEDICAL SCHOOL · 2024 · $187,056

## Abstract

Project Summary
 The immune system is capable of mounting a robust anti-cancer response. However, cancer cells can
disrupt this immune response, hijacking immune checkpoint mechanisms which act as brakes on the
endogenous anti-cancer response. Antibodies that block immune checkpoints (e.g., a-PD-L1, a-PD-1, and a-
CTLA4) have revolutionized cancer treatments, yet, only a fraction of patients respond. Understanding the
underlying mechanisms that promote a durable anti-tumor response to checkpoint blockade therapy is crucial
to develop effective therapeutics that can treat a wider range of cancer patients. The gut microbiota is a key
variable in the anti-tumor response to immunotherapy, even for tumors outside of the intestine. The goal of this
project is to identify gut bacterial molecules that promote an anti-tumor response to PD-1 blockade and their
mechanisms of action. I hypothesize that certain gut bacterial surface components prime immune cells and
these bacterial-immune interactions within the gut are essential for the anti-tumor immune response to PD-1
blockade at extra-intestinal sites. I propose to test this hypothesis by determining the key immune components
of the microbe-dependent immune response in the tumor (Aim 1), the key bacterial molecules which promote
the anti-tumor response (Aim 2), and the mechanisms by which microbes and immune cells interact within the
gut (Aim 3). These studies are significant because by identifying active, anti-tumor gut bacterial molecules and
mechanisms, more effective therapeutics can be developed that will broaden the range of patients who
respond to checkpoint therapy.
 My long-term goal is to run a research group that investigates the interactions between gut bacteria and
the immune system. My motivation is to identify new bacterial molecules and their mechanisms of action that
can be harnessed in the clinic as therapeutics for cancer and other diseases. I trained in Dennis Kasper’s lab
gaining expertise in gnotobiotic mouse work, microbiota analysis and culture, click chemistry, and bacterial
molecule separation leading to the preliminary data for Aims 1-3. To learn about the immune response to PD-1
blockade and co-signaling molecules, I collaborated with Arlene Sharpe’s lab and obtained preliminary data for
Aims 1-3. This collaboration has led to two patent applications and discussions with industry for drug
translation. To understand how bacteria directly interact with gut cells, I developed a mouse microfluidic gut
chip in a collaboration with Donald Ingber’s lab at the Wyss institute at Harvard that I plan to use in Aims 2 and
3. By taking advantage of the excellent work environment at Harvard Medical School, I have acquired a
unique skill set stemming from experience with both the academic research environment and with industry
discussions for clinical translation. This training enables me to run my own research group that will investigate
gut bacterial/immune interactions that can be employe...

## Key facts

- **NIH application ID:** 10884884
- **Project number:** 5K22CA258960-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Francesca Smylie Gazzaniga
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $187,056
- **Award type:** 5
- **Project period:** 2022-08-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884884

## Citation

> US National Institutes of Health, RePORTER application 10884884, Identifying gut bacterial molecules and mechanisms that promote an anti-tumor response to immunotherapy (5K22CA258960-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10884884. Licensed CC0.

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