# Overcoming the immune evasion mechanism of Merkel cell polyomavirus-associated Merkel cell carcinoma

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $260,509

## Abstract

Project Summary
Tumor immune escape represents a major obstacle in cancer immunotherapy, however, the
underlying mechanism remains poorly understood. The goal of this exploratory research
proposal is to overcome the immune evasion mechanism of Merkel cell carcinoma (MCC), a
highly lethal skin cancer associated with merkel cell polyomavirus (MCPyV). Currently, there is
no effective therapeutic treatment for metastatic MCCs. A large portion of MCCs is resistant to
the immune checkpoint therapies. Immuno-suppression is an important risk factor for MCPyV-
associated MCC. Furthermore, in more than 90% of MCC patients with normal immune function,
MCC tumors continue to develop despite the production of T cells recognizing MCPyV-encoded
oncoproteins expressed in the tumors. Tumor-infiltrating MCPyV-specific T cells are critical for
improved patient survival, and yet they are sparsely present in a very small percentage of MCCs
and show significantly reduced activation. These observations support that MCPyV-associated
MCCs may escape immunological destruction by restricting T-cell intratumoral infiltration and
repressing T cell activation. However, the underlying mechanisms are largely unknown. We
recently discovered that Stimulator of Interferon Genes (STING) is completely silenced in
MCPyV+ MCCs. Because STING function is critical for sensing damaged DNA in cancer cells to
stimulate cytokine production, intratumoral CD8+ T cell infiltration, and antitumor T cell
responses, we hypothesize that STING silencing in MCC contributes to its immune suppressive
nature and that reactivation of STING in MCCs can stimulate T cell infiltration and antitumor
cytotoxicity. To test this hypothesis, we have developed a novel approach to specifically activate
STING in MCC but not other human cells. This approach will be combined with engineered
human T cells, an MCC mouse xenograft model, as well as a humanized mouse tumor model to
define the functional impact of STING reactivation on stimulating T cell intratumoral infiltration
and antitumor immune responses. Because STING signaling is also important for enhancing the
antitumor efficacy of checkpoint inhibitors, we will combine our new STING-reactivating method
with PD-1 blockade to achieve synergistic antitumor activity and circumvent MCC resistance to
immune checkpoint therapies. These studies have the potential to overcome the MCC
immunoescape mechanism and develop novel therapeutic strategies to treat the highly
aggressive MCC cancers. Our study may also reveal a novel strategy for overcoming the
toxicity and limitation of traditional human STING agonist-based therapies.

## Key facts

- **NIH application ID:** 9894065
- **Project number:** 1R21AI149761-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jianxin You
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $260,509
- **Award type:** 1
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894065

## Citation

> US National Institutes of Health, RePORTER application 9894065, Overcoming the immune evasion mechanism of Merkel cell polyomavirus-associated Merkel cell carcinoma (1R21AI149761-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894065. Licensed CC0.

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