# Ontogeny and Function of Tumor-Resident Innate Lymphocytes and Innate-Like T Cells

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $500,820

## Abstract

Project Summary
Cancer immunosurveillance ascribes a role of the immune system in repressing tumor development. Cancer
immunotherapy approaches such as checkpoint blockade that revives this function of exhausted T cells have
revolutionized cancer patient care. Nonetheless, many patients do not respond to this modality of cancer
treatment, calling for investigation of a broader spectrum of tumor-elicited immune responses. We have
recently shown that tumor growth induces expansion of tissue-resident cytotoxic innate lymphocytes and
innate-like T cells that share a gene expression program distinct from that of NK cells and exhausted T cells.
Characterized by high expression of the transcription factor Hobit and cytolytic granzymes, these cells are
herein named killer innate lymphoid cells (ILCk) and killer innate-like T cells (ILTCk). Notably, genetic depletion
of ILCk and ILTCk results in accelerated tumor growth. Furthermore, tumor cells express high levels of IL-15
and lose E-cadherin polarity, and IL-15 or E-cadherin deficiency depletes ILCk and ILTCk resulting in
accelerated tumor growth. Based on these findings, we hypothesize that ILCk and ILTCk are novel lineages of
cytotoxic lymphocytes, and they function as sentinels of cell transformation by sensing tumor cell-derived IL-15
and E-cadherin. To test this hypothesis, we will first define the developmental pathways of ILCk and ILTCk. By
performing cell transfer and cell fate-mapping experiments as well as using mice deficient in lineage-specifying
transcription factors, we will assess whether ILCk are differentiated along the innate lymphoid cell lineage. In
addition, we will generate T cell receptor (TCR) retrogenic mice and perform TCR “swapping” experiments to
determine whether distinct thymic selection promotes ILTCk differentiation. Parabiosis and inducible
hematopoietic stem cell-targeted cell fate-mapping experiments will also be performed to determine whether
ILCk and ILTCk are continuously generated throughout tumor progression. Secondly, we will define the
function and regulation of ILCk and ILTCk by initially assessing whether Hobit expression marks a stage of
functional specification, and whether Hobit controls a gene expression program essential for ILCk and ILTCk-
mediated cancer surveillance. In addition, we will utilize conditional null alleles of Il15 and Il2rb and a gain-of-
function allele encoding an active form of the transcription factor Stat5b to determine whether tumor IL-15
functions as an alarmin for ILCk and ILTCk, and whether IL-15 signaling constitutes a rate-limiting step of the
ILCk and ILTCk response. Finally, we will investigate the interactions between tumor cells and ILCk and ILTCk
by intravital imaging, and assess whether E-cadherin is sensed by the TGF-b-induced integrin CD103, and
whether patient CDH1 hot-spot missense mutations promote tumor evasion from ILCk and ILTCk-mediated
cancer surveillance. Successful completion of this project will not only gene...

## Key facts

- **NIH application ID:** 10415158
- **Project number:** 5R01CA243904-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ming Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $500,820
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415158

## Citation

> US National Institutes of Health, RePORTER application 10415158, Ontogeny and Function of Tumor-Resident Innate Lymphocytes and Innate-Like T Cells (5R01CA243904-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10415158. Licensed CC0.

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