# Role of the gut microbiome in modulating the efficacy of checkpoint blockade therapy

> **NIH NIH F32** · UNIVERSITY OF CHICAGO · 2020 · $69,306

## Abstract

Project Summary
 The implementation of checkpoint blockade immunotherapy is having a major
impact on cancer outcomes. However, a sizable subset of patients still fails to benefit,
and prior research has shown that inadequate baseline T cell infiltration into the tumor
microenvironment is associated with lack of clinical response. These findings point to
poor spontaneous T cell activation and recruitment as a general mechanism of
resistance and motivate the search for mechanisms that regulate the degree of T cell
infiltration into the tumor microenvironment. Our group has previously identified tumor-
intrinsic oncogene pathways as key variables that contribute to poor T cell recruitment
and therapeutic resistance. Host-intrinsic factors such as germline polymorphisms in
immune regulatory genes can also influence the degree of T cell infiltration. But in
addition, a major environmentally-influenced variable has recently emerged, which is
the composition of the commensal microbiota. Recent work in our group has identified
the commensal microbiota as a key determinant of anti-tumor immunity and
immunotherapy efficacy in a mouse melanoma model (Sivan et al. Science 2015).
Based on that work, we pursued a similar correlation in human melanoma patients
undergoing anti-PD-1 immunotherapy and found a profound correlation between
baseline microbiota composition and clinical response, which was a significant
biomarker for predicting treatment outcome (Matson et al. Science 2015). We further
demonstrated a deeper causal link by colonizing germ-free mice with responder or non-
responder patient microbiomes, which recapitulated the strong or poor therapeutic
response to PD-1 blockade, which correlated with the degree of spontanaoues T cell
priming against the tumor. In the current proposal, we will employ this model system to
further pursue the mechanisms by which the commensal microbiota from humans
modulates the anti-tumor immune response in vivo. A major goal is to identify the gut
microbiota-driven messenger(s) capable of transmitting the immunomodulatory effect to
the tumor site. Understanding these deeper mechanisms of immune potentiation could
enable development of drugs that mimic the presence of immune-potentiating bacteria.
Another major goal is to isolate and culture the human-derived commensal bacteria with
immune-potentiating properties. This effort could lead to the development of probiotics
to supplement immunotherapy regimens and improve outcomes in the future.

## Key facts

- **NIH application ID:** 9852878
- **Project number:** 5F32CA236296-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Vyara Matson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852878

## Citation

> US National Institutes of Health, RePORTER application 9852878, Role of the gut microbiome in modulating the efficacy of checkpoint blockade therapy (5F32CA236296-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852878. Licensed CC0.

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