# Understanding the role and clinical potential of dominant immune suppressive myeloid-cell responses in human cancer

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $375,493

## Abstract

Lung and colorectal cancer are among the top three most deadly malignancies and together they account for
~32% of all cancer-related fatalities. Although anti-cancer immunotherapy using PD-1 and CTLA-4 blocking
antibodies shows prominent activity and has been approved for use in multiple tumors, most patients show
treatment resistance and there are striking differences in the clinical activity across tumor types. Currently, the
determinants for treatment sensitivity/resistance and the difference in the role of dominant immune evasion
pathways across cancers are uncertain. To substantially reduce lung and colorectal cancer mortality, it is
imperative to: i) Identify novel biomarkers for optimal selection of patients for treatment; ii) Uncover
immunotherapy targets beyond the PD-1/CTLA-4 pathways that may serve to treat patients with refractory
tumors; and iii) Reveal the role of immunity during tumor progression to design early therapeutic interventions.
Recent studies from our group identified the IL-8/CXCR1/CXCR2 pathway as a strong determinant for negative
immune modulation and therapeutic resistance to immune checkpoint blockers. The immune suppressive
effects of the IL-8 pathway involve increased neutrophils in the tumor niche and local development of
neutrophil extracellular traps (NETs). We hypothesize that the deleterious effects of the IL-8 pathway in the
tumor immune microenvironment are promoted by local metabolic suppression. We anticipate these responses
to be different in tumors with distinct immune properties and sensitivity to immune checkpoint blockers such as
lung and colorectal cancer; and during early stages of tumor development. In this project and through 3
complementary aims, we will leverage our expertise in cancer immunobiology and translational research to: i)
Determine the metabolic/immune context and biomarker value of the IL-8 pathway and myeloid-cell responses
in cancer; ii) Analyze the mechanisms and role of IL-8 induced NET formation as negative immunomodulatory
event in human malignancies; and iii) Examine the role of the IL-8 pathway and immune contexture in
carcinogenesis and early cancer progression. The results from this work will accelerate translation of research
concepts into the clinic for establishment of novel biomarkers, support interpretation of clinical trials and design
optimal treatment modalities for early-stage and advanced tumors.

## Key facts

- **NIH application ID:** 10487541
- **Project number:** 5R01CA262377-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kurt A Schalper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,493
- **Award type:** 5
- **Project period:** 2021-09-10 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487541

## Citation

> US National Institutes of Health, RePORTER application 10487541, Understanding the role and clinical potential of dominant immune suppressive myeloid-cell responses in human cancer (5R01CA262377-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487541. Licensed CC0.

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