# Identifying Immune Mechanisms for Microbiota-Inhibition of Anti-PD-L1 Tumor Response

> **NIH NIH F30** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $51,036

## Abstract

PROJECT SUMMARY
Immune checkpoint blockade is a recent cancer therapeutic strategy that has enabled durable responses in 15-
40% of patients for several cancers by licensing CD8+ tumor infiltrating lymphocytes to kill tumor cells. Despite
dramatically altering the clinical course in a subset of patients, these drugs fail to elicit durable response in the
majority of cancer patients. The human microbiota is thought to regulate immune tone or responsiveness, and
thus is a promising, modifiable target to improve checkpoint blockade response rates. Indeed, response rates
for epidermal malignancies to anti-PD-1 have been associated with fecal microbial diversity, and patients’ prior
use of antibiotics. Moreover, particular bacterial isolates have been identified in mice that can
disproportionally contribute to tumor immune responses following anti-CTLA-4 and anti-PD-L1 therapy.
While the potential importance of microbiota manipulation for checkpoint blockade response is clear, much
work remains to be done to determine how these microbiota-dependent immune responses to cancer are
generated and maintained. To begin understanding how the microbiota-immune interface in the gut can
contribute to the immune activity and anti-PD-L1 response of non-mucosal malignancy, I have established a
humanized gnotobiotic model of anti-PD-L1 treated melanoma. I have demonstrated that a defined microbial
community can inhibit B16 melanoma response to anti-PD-L1. This grant aims to dissect the yet
unknown mechanisms that mediate this microbiota-dependent inhibition of tumor response to
anti-PD-L1 by evaluating the functions and phenotypes of several immune cell populations in the
tumor and tumor draining lymph node. Aim 1—Based on my preliminary data we have selected two defined
microbial communities that result in contrasting tumor growth rates when colonized into germfree, B16
melanoma-bearing mice. I aim to evaluate the influence of intestinal microbiota on anti-tumor T cell
responses following checkpoint blockade therapy by exploring possible differences in tumor-immune
architecture, modifications to T cell proliferation and killing of tumor cells, depletion of key T cell subsets and
regulators in vivo, and metagenomic profiling before and after anti-PD-L1 treatment. Aim 2—The adaptive
immune response is dependent upon priming and activation by myeloid cells, which in turn are modified by
microbial sensing machinery. We hypothesize that alterations in myeloid cell functions and
phenotypes regulate the adaptive response to anti-PD-L1. To evaluate these cells I will preform
transcriptomic and proteomic analysis of macrophages and dendritic cells in the tumor and draining lymph
node, assess response causal dependency through myeloid subset depletion, and evaluate the priming ability of
dendritic cells from responding and nonresponding gnotobiotic mice. By studying these gnotobiotic animals
with different clinical responses to checkpoint blockade, we hope to uncover the me...

## Key facts

- **NIH application ID:** 10069313
- **Project number:** 5F30CA235963-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Joshua Borgerding
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-12-24 → 2022-12-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069313

## Citation

> US National Institutes of Health, RePORTER application 10069313, Identifying Immune Mechanisms for Microbiota-Inhibition of Anti-PD-L1 Tumor Response (5F30CA235963-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10069313. Licensed CC0.

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