# Mechanism of microbiota-mediated potentiation of checkpoint blockade efficacy in lung cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $560,724

## Abstract

The discovery that the host immune system can be harnessed to attack solid tumors and improve overall
survival for patients has been transformative. However, only certain tumors are responsive to immune
checkpoint blockade, and an unpredictable fraction maintain durable remissions. In addition, similarly
unpredictable toxicity can manifest with diverse autoimmune attack of normal tissue. Beyond PD-L1 staining
and mutational burden, we have limited biomarkers of response, and we have no predictors of autoimmune
toxicities. Recent studies have highlighted the contribution of the intestinal microbiota to successful PD-1/PD-
L1 and CTLA-4 antibody blockade. There is, however, no consensus as to which microbes promote effective
anti-tumor immune responses, and we lack an understanding of the mechanisms involved. In our proposed
studies, we will seek to identify human gut-associated bacterial species and products that enhance control of
lung adenocarcinoma growth following anti-PD-1 immunotherapy. We will then characterize the host cellular
and molecular targets of the bacteria and their products. In preliminary studies, we identified a strain of
Bacteroides vulgatus that promotes autoimmune disease and also restricts growth of implanted lung cancer
cells in anti-PD-1-treated mice. This tumor model will be used to assess the immune-potentiating roles of B.
vulgatus genes, such as those involved in synthesis of capsular polysaccharides and Lipid A, and to screen
bacterial libraries prepared from patient super-responders, to identify species and consortia that are most
effective at supporting inhibition of tumor growth. We have also developed an autochthonous lung cancer
model in which neoantigens accumulate due to targeting of the mismatch repair machinery, and we will assess
the ability of the candidate microbes to function in a therapeutic mode, after growth of the spontaneous tumors
is established. We will then characterize differences in metabolites and proteins within lymph draining the
intestine of mice colonized with immunotherapy-potentiating or control microbes, and candidate molecules will
be evaluated for their activity in the tumor models. Lastly, we will seek to identify the innate signaling pathways
and the relevant host target cells that convey microbial signals to the tumor microenvironment, thus enhancing
immune control of tumor growth following anti-PD-1 administration. Since tumor cell killing is mediated by
cytotoxic T cells, we will also determine if there are shared antigenic specificities between tumors and the
microbiota. These studies will be complemented by spatial transcriptomic analyses of tumor
microenvironments from mice with and without immunotherapy-potentiating microbiota. Serum from responder
and non-responder lung cancer patients will be evaluated for the presence of microbiome-dependent products
identified in the mouse model and tumor tissue specimens will be subjected to spatial transcriptomics analysis
to determine ...

## Key facts

- **NIH application ID:** 10436388
- **Project number:** 5R01CA255635-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Dan Littman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $560,724
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436388

## Citation

> US National Institutes of Health, RePORTER application 10436388, Mechanism of microbiota-mediated potentiation of checkpoint blockade efficacy in lung cancer (5R01CA255635-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436388. Licensed CC0.

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