# Role of the Gut Microbiota in Regulating Responses to anti-PD-1 Cancer Immunotherapy

> **NIH NIH F32** · HARVARD MEDICAL SCHOOL · 2022 · $73,942

## Abstract

Project Summary
Commensalism in the gut has been suggested to influence many aspects of human health and diseases. It is
now widely accepted that gut commensal microbes have a crucial impact on immune homeostasis in the gut.
Emerging evidence suggest that the gut microbiota shapes systemic immunity, but the underlying mechanisms
are poorly understood. Recent reports from other groups and our preliminary findings indicate that the gut
microbiome and its composition are important factors that determine responsiveness to immune checkpoint
blockade 1-3. Immune checkpoint inhibitors are novel therapeutic interventions which reinvigorate tumor-
specific T cells to attack tumor cells by targeting co-inhibitory pathways in T cells, such as PD-1:PD-L1 and
CTLA-4. Despite the clinical success of these checkpoint blockade immunotherapies, a significant fraction of
patients do not respond to the checkpoint inhibitors 4. Recent studies showed that one of the critical
determinants of responsiveness to checkpoint blockade may be the composition of the gut microbiome.
However, how the gut microbiota modulates systemic immune responses to tumor is not known. The goals of
this project are to determine mechanisms by which the gut microbiome regulates anti-tumor immunity and
response to PD-L1 blockade. To achieve these goals, we will 1) Use gnotobiotic techniques and antibiotics to
identify human gut microbes that promote tumor clearance upon PD-L1 blocking antibody treatment; 2)
elucidate cellular and molecular mechanisms of gut microbiota dependent anti-tumor immunity, focusing on
how changes in the gut microbiota controls co-inhibitory pathways that regulate anti-tumor immunity; and 3)
investigate how microbial products from the gut contribute to anti-tumor immunity. The proposed study will
provide critical insights into mechanisms by which the gut microbiota regulates anti-tumor immunity, and new
therapeutic strategies for patients who do not respond to PD-1 pathway blockade.

## Key facts

- **NIH application ID:** 10310476
- **Project number:** 5F32CA247072-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Joon Seok Park
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $73,942
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310476

## Citation

> US National Institutes of Health, RePORTER application 10310476, Role of the Gut Microbiota in Regulating Responses to anti-PD-1 Cancer Immunotherapy (5F32CA247072-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10310476. Licensed CC0.

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