# Innate lymphoid cell regulation of the host-microbiota interactions in cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $551,090

## Abstract

PROJECT ABSTRACT
Host-microbe interactions profoundly impact cancer. This is exemplified by well-documented infections that
promote cancer, and the ability to prevent these cancers through vaccination or pathogen avoidance. However,
humans are densely colonized with trillions of normally beneficial microbes, termed the microbiota, which also
have the ability to promote cancers through the induction of inflammation or genomic instability. Further, recent
seminal studies demonstrated that intestinal microbiota are also required for anti-tumor immunity in the context
of therapeutic interventions, such as checkpoint blockade. Despite these advances, the specific pathways by
which microbiota shape pro- versus anti-tumor immunity remain poorly defined, and the potential relevance of
these findings to specific types of cancer are unknown. The fundamental focus of this proposal is to
mechanistically define a novel pathway that controls host-microbiota interactions to protect from
tumor progression and promote the efficacy of immunotherapies in colorectal cancer (CRC). In recently
published data (Goc et al., Cell, 2021), we have determined that group 3 innate lymphoid cells (ILC3s) are
fundamentally altered in CRC and contribute to tumor progression and immunotherapy responsiveness by
coordinating host-microbiota interactions. These data provoke a fundamental hypothesis that intestinal ILC3s
are protective in cancer, but become inherently disrupted in CRC, subsequently driving dysfunctional adaptive
immunity and alterations to the microbiota that support tumor progression and immunotherapy resistance. We
will mechanistically test this hypothesis by asking the following specific questions: (1) What drives dysfunction
of ILC3s in CRC?; (2) What are the microbial and host pathways by which ILC3s protect from tumor
progression?; And (3) What are the microbial and host pathways by which ILC3s protect from immunotherapy
resistance? Finally, we will directly test a number of interventional strategies that target the microbiota to limit
tumor progression and break resistance to cancer checkpoint inhibitors. Results from these experiments will
pave the way for a greater understanding of host-microbiota interactions in cancer, and could provoke novel
preventative, therapeutic or curative strategies in cancer by modulating host-microbiota interactions.

## Key facts

- **NIH application ID:** 10898057
- **Project number:** 5R01CA274534-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Gregory F Sonnenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $551,090
- **Award type:** 5
- **Project period:** 2022-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898057

## Citation

> US National Institutes of Health, RePORTER application 10898057, Innate lymphoid cell regulation of the host-microbiota interactions in cancer (5R01CA274534-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898057. Licensed CC0.

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