# Elucidating mechanisms of mucin-mediated immune regulation in cancer

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $51,657

## Abstract

Project Summary
Despite the remarkable benefits of cancer immunotherapies observed in select cases, many patients and
cancers are unresponsive or develop resistance to existing treatments. There is emerging evidence that mucins,
large cell-surface glycoproteins which are frequently upregulated in cancer, allow tumors to resist treatment with
immunotherapies by engaging an inhibitory glycan-binding receptor on immune cells called Siglec-9. However,
the molecular epitopes involved in mucin-Siglec-9 binding remain poorly understood due to historical challenges
associated with studying receptor-glycoprotein interactions. This proposal seeks to develop new approaches to
interrogate the role of mucins as immunological regulators by building upon high-resolution mucin mass
spectrometry and cutting-edge precision glycoprotein synthesis techniques. Specifically, I will develop a coupled
immunoprecipitation and mass spectrometry workflow to identify mucin glycopeptide epitopes that interact with
Siglec-9 from both recombinant mucins and those derived from diverse human tumor cell lines (Aim 1). In
parallel, I will carry out high-throughput screens of synthetic glycopeptide arrays bearing defined glycan
structures to comprehensively elucidate the structural determinants of Siglec-9 binding (Aim 2). Finally, I will
characterize the binding site of Siglec-9 via co-crystallization with a mucin-mimetic glycopeptide and use insights
gained to develop and validate candidate glycopeptide inhibitors of the mucin-Siglec-9 immune synapse (Aim
3). This work will shed light on a previously understudied mechanism of immune evasion exploited by a significant
fraction of tumors, with the potential to identify novel cancer immunotherapy agents that could increase the
number of patients who benefit from treatment.

## Key facts

- **NIH application ID:** 9990261
- **Project number:** 1F32CA250324-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jessica C Stark
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $51,657
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990261

## Citation

> US National Institutes of Health, RePORTER application 9990261, Elucidating mechanisms of mucin-mediated immune regulation in cancer (1F32CA250324-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990261. Licensed CC0.

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