# Immunoregulatory role of lung-resident club cell factors in lung cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $645,197

## Abstract

Abstract
Despite advances in surgery, radiotherapy, and molecular targeted therapies, mortality in non-small
cell lung cancer (NSCLC) remains high. Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-
L1 axis have been approved for the treatment of advanced NSCLC, yet >70% of the patients
experience little clinical benefit due to a variety of immunosuppressive barriers in the tumor
microenvironment (TME). Myeloid suppressor cells exert potent immunosuppressive activity in the
TME that promotes tumor progression, mediates resistance to immunotherapy, and confers poor
outcomes in a variety of cancer types. We have shown that low dose stereotactic body radiation
therapy (SBRT) in combination with ICI confers durable anti-tumor immunity resulting in marked
tumor regression and improved survival in mouse models of NSCLC. Unexpectedly, we uncovered
that SBRT-mediated activation of lung resident Scgb1a1+ club cell secretome is necessary for
improving the efficacy of ICI. We identified a set of 8 club cells secretory factors which in
combination with PD-1 blockade elicited significant tumor control and improved survival.
Mechanistically, club cell factors inhibit myeloid suppressor cells, reduce pro-tumor inflammatory
mediators to improve the effectiveness of ICI. Consistent with the preclinical findings, NSCLC
patients who responded to neoadjuvant SBRT/ICI therapy showed increased plasma CC10, a member
of the club cell secretome factor. These findings have led to the hypothesis that club cell factors
selectively inhibit immunosuppressive and proinflammatory function of myeloid suppressor cells to
increase the efficacy of immune checkpoint blockade. We further hypothesize that club cell factors
may serve as biomarkers of response and recurrence to SBRT/ICI therapy in human NSCLC.
Using an integrated preclinical and clinical approach, we will test this hypothesis through two
specific aims. Aim 1 will determine the exact identity of the core club cell factor/s and elucidate
mechanisms by which they attenuate myeloid suppressor cells to generate durable anti-tumor
immunity, and Aim 2 will leverage samples from a clinical trial to determine if club cell-based
biomarkers are associated with response therapy and metastatic recurrence following ICI/SBRT
therapy in human NSCLC. This work will develop a mechanism-based rationale for the development
of club cell factors as selective inhibitors of myeloid suppressor cells and for improving the efficacy
of ICI in NSCLC.

## Key facts

- **NIH application ID:** 10770500
- **Project number:** 5R01CA271545-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** NASSER Khaled ALTORKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $645,197
- **Award type:** 5
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770500

## Citation

> US National Institutes of Health, RePORTER application 10770500, Immunoregulatory role of lung-resident club cell factors in lung cancer (5R01CA271545-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10770500. Licensed CC0.

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