# MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $624,332

## Abstract

Non-small cell lung cancers (NSCLCs), particularly those with activating KRAS mutations, are often
unresponsive to targeted agents and have a poor prognosis. However, immunotherapeutic approaches,
particularly PD-1/PD-L1 pathway blockade, have recently improved the treatment of these cancers, supporting
the premise that evasion of immune destruction contributes to NSCLC pathogenesis. MUC1-C is an
oncogenic protein that is overexpressed in >80% of NSCLCs and is linked to multiple immune signaling
pathways.
Work supported by this grant has demonstrated that EGFR mutant NSCLCs activate the PD-1/PD-L1 pathway
and increase production of proinflammatory cytokines. We have also shown that MUC1-C promotes (i)
oncogenic signaling in NSCLCs via EGFR activation, and (ii) confers EMT, self-renewal and tumorigenicity in
KRAS mutant NSCLCs. Based on these findings, we have generated novel antibodies against the non-shed
MUC1-C extracellular domain and inhibitors of the cytoplasmic domain for therapeutic targeting of MUC1-C in
NSCLC cells.
Our preliminary observations indicate that targeting MUC1-C downregulates PD-L1 expression in EGFR and
KRAS mutant NSCLC cells. We have also found that MUC1-C deficiency is associated with recruitment of
tumor-associated macrophages and alterations in the infiltrating T-cell phenotype. Our hypothesis is that
MUC1-C plays an important role in evading immune destruction, which will be addressed in studies of (i)
human NSCLC cell lines, (ii) genetically engineered mouse models, and (iii) primary NSCLC tumors.
The Specific Aims are: (1) To investigate the role of MUC1-C in PD-L1 pathway activation in EGFR and KRAS
mutant NSCLC cells, (2) To define the role of MUC1-C in recruitment and function of macrophages and T-cells
within the tumor microenvironment of KRAS and EGFR mutant NSCLC, (3) To evaluate the effects of targeting
MUC1-C to circumvent immune evasion in mutant EGFR and KRAS NSCL tumors, and (4) To assess fresh
resected/biopsied lung cancer specimens and correlate MUC1 expression with T-cell and other immune cell
infiltration, immune checkpoint gene expression, and cytokine secretion in the tumor microenvironment.

## Key facts

- **NIH application ID:** 9913473
- **Project number:** 5R01CA166480-09
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** DONALD W. KUFE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $624,332
- **Award type:** 5
- **Project period:** 2012-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913473

## Citation

> US National Institutes of Health, RePORTER application 9913473, MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer (5R01CA166480-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9913473. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*