# Role of Gut Microbiota in Modulating Immune Checkpoint Inhibitory Therapy for Cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $596,098

## Abstract

Immune checkpoint inhibitor therapy (ICT) unleashes the immune system resulting in durable remissions in up
to 50% of patients with previously incurable cancers, such as metastatic melanoma. But the host factors that
modulate or dictate ICT response are poorly understood. Recent, preclinical data suggests that specific gut
microbiota are required for optimizing response to ICT. These commensal gut microbiota augment host
adaptive immune responses, specifically host immune cells, needed for anti-cancer activity. We recently
showed that adult melanoma patients who respond to ICT have a distinct gut microbiota signature compared to
patients with progressive disease. In preliminary data, we demonstrated that precision probiotic therapy (using
the specific bacteria that we identified in our clinical/translational study) augmented the efficacy of ICT in mice
with melanoma whereas a probiotic commonly found in yogurt did not. Microbiota dictated a reduction in PD-1
expressing CD4 and CD8 T cells in mesenteric lymph nodes (MLNs) following ICT. Of note, these specific gut
microbiota had a greater number of protein sequences homologous to human melanoma neoantigens when
compared to the ineffective yogurt probiotic. Further, these gut microbiota induced CD4 and CD8 T cell
production of IFN-gamma and Granzyme B. Interestingly, mice without draining lymph nodes in the gut did not
respond to ICT. ICT promoted gut microbiota translocation into MLNs. Finally, oral administration of heat-killed
gut microbiota did not augment ICT efficacy, suggesting that live bacteria are required for augmenting ICT.
Therefore, our central hypothesis is that only gut microbiota that have both high immunogenic potential and the
ability to translocate into the abdominal draining lymph nodes will facilitate activation/education of immune cells
and thus augment ICT efficacy. To test this hypothesis, we will pursue the following three specific aims. First,
we will further define both gut microbiome and tumor genetic differences in melanoma patients who respond to
ICT compared to those with disease progression. Second, we will identify environmental and microbial factors
that dictate gut microbiota translocation into mesenteric lymph nodes. Third, we will elucidate the mechanisms
by which gut microbiota modulate host immune cell anti-tumor response by performing in vitro functional
immune cell assays to determine if and how specific gut microbiota prime immune cells and in vivo studies to
identify the specific immune cells recruited by gut microbiota. These studies will lay the groundwork for the
following innovations: 1) a novel mechanism by which gut microbiota activate immune defenses against cancer
and 2) a novel approach (precision probiotics) for optimizing ICT efficacy in advanced cancer patients.

## Key facts

- **NIH application ID:** 10246933
- **Project number:** 5R01CA231303-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jade Homsi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $596,098
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246933

## Citation

> US National Institutes of Health, RePORTER application 10246933, Role of Gut Microbiota in Modulating Immune Checkpoint Inhibitory Therapy for Cancer (5R01CA231303-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10246933. Licensed CC0.

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