# Project 3: Adaptive immunity to MCPyV in Merkel cell carcinoma

> **NIH NIH P01** · UNIVERSITY OF WASHINGTON · 2022 · $454,020

## Abstract

Summary: Project 3
 Merkel cell polyomavirus (MCPyV)-positive Merkel cell carcinoma (MCC) presents a significant and timely
opportunity to address basic questions in tumor immunology. Almost uniquely amongst human cancers, in
virus-positive MCC (VP-MCC), a) a non-self, viral antigen is required for cell transformation, b) these
oncoproteins are small and have few polymorphisms, c) the tumor mutation burden is very low, d) detection of
viral oncoprotein-specific CD4 and CD8 T- and B-cells is very frequently possible, and e) biopsies are
commonly obtained. Our studies of T-cell responses to the MCPyV T-antigen (T-Ag) provided the rationale for
trials of anti-PD-1 therapy. These recently FDA-approved therapies have improved outcomes for many persons
with advanced disease. Project 3 focuses on persons with local or regional disease, who collectively have a
37% chance of recurrence at 18 months after current standard therapy.
 Project 3 is led by an experienced viral immunologist and member with the P01 team. Our medical center
is a well-established referral center for MCC, such that archived specimens from patients with known outcomes
are available and 70-80 new patients are enrolled annually. To closely dissect the relationship between
MCPyV-specific acquired immunity and outcomes, we propose three Aims. Aim 1 will determine the
relationship between T-Ag-specific CD8 T-cell phenotype including dysfunction and avidity, with clinical
outcomes, in persons with early-stage MCPyV (+) MCC. Aim 2 will conduct similar studies of the T-Ag-specific
CD4 T-cells, including quantitative measures of tumor CD4 infiltration at the cell and molecular levels, and
measurement of CD4 T helper phenotype. T-cell studies will focus on both TIL and blood, the site of both
profound tumor-antigen specific T-cell localization and dysfunction. Results will be correlated with
immunohistochemical studies of the suppressive tumor microenvironment. Aim 3 addresses the antibody
response to T-Ag, which waxes and wanes with tumor burden in persons with MCPyV (+) MCC. Rising serum
anti-T-Ag IgG presages tumor relapse and serial testing is included in 2018 NCCN guidelines for MCC care. T-
Ag-specific B cells will be detected in blood using novel tetramer reagents and studied by IgG sequencing and
detailed immunophenotyping. Our group has detected somatic hypermutation in the IgG genes of validated T-
Ag-specific B-cells, indicating that these cells have traversed the germinal center, yet fail to differentiate into
long-lived antibody secreting cells, a very unusual pattern. The underlying Premise of Project 3 is that insights
we will deliver regarding adaptive immunity in VP-MCC will be generally applicable to malignancies that are harder
to study because their tumor antigens are seldom conserved among patients.

## Key facts

- **NIH application ID:** 10380819
- **Project number:** 5P01CA225517-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** David M Koelle
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $454,020
- **Award type:** 5
- **Project period:** 2019-04-04 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380819

## Citation

> US National Institutes of Health, RePORTER application 10380819, Project 3: Adaptive immunity to MCPyV in Merkel cell carcinoma (5P01CA225517-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380819. Licensed CC0.

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