# Role of melanoma-PD-1 in cancer progression

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $395,502

## Abstract

Therapeutic antibodies targeting the programmed cell death 1 (PD-1) pathway have shown remarkable efficacy
in the treatment of advanced melanoma. Consequently, the United States Food and Drug Administration
recently approved two PD-1 inhibitors for the treatment of patients with advanced melanoma who no longer
respond to other drugs. However, anti-PD-1 therapy does not translate into long-term disease control in most
patients, highlighting the need for mechanistic insights and biomarkers that predict and help optimize clinical
benefit. Because PD-1 has mainly been studied in immune cells, the majority of research regarding its role in
melanoma and the identification of biomarkers for predicting response to PD-1 inhibitors has focused on
immune cell-associated PD-1 functions and their immunologic and molecular correlates. We have recently
demonstrated that PD-1 is not only expressed by immune cells, but also by melanoma cells. Melanoma-
expressed PD-1 serves as a cancer cell-intrinsic growth receptor that activates oncogenic signaling and
promotes tumorigenesis. Inhibition of melanoma-PD-1 suppresses tumor growth, even in mice lacking adaptive
immunity. In patients with stage IV disease, tumoral expression of melanoma-PD-1 receptor targets correlates
with clinical response to PD-1 inhibition. Our preliminary studies identify novel PD-1 pathway functions in tumor
growth and suggest that melanoma-PD-1 blockade might contribute to the clinical efficacy of anti-PD-1
therapy. Therefore, we propose to define the precise mechanisms through which the melanoma-PD-1 receptor
promotes tumor progression and examine how the melanoma cell-intrinsic PD-1 signaling axis might be
exploited for predicting and optimizing treatment response to therapeutic PD-1 antibodies. Our specific aims
are to 1) define melanoma cell-intrinsic PD-1 signaling networks required for cancer progression and 2) to
examine the utility of melanoma-PD-1 signaling mediators as biomarkers of clinical response to anti-PD-1
therapy. We will use several state-of-the-art gain- and loss-of-function approaches, including mutagenesis of
melanoma-PD-1 signaling motifs, knockdown, overexpression, antibody-mediated and pharmacologic inhibition
or activation of PD-1 pathway members in melanoma and immune cells, as well as PD-1 and PD-1 ligand
knockout mice, with or without functional immunity, to define the immunologic, molecular, and cellular factors
required for melanoma-PD-1-dependent tumorigenesis. Our initiative will also implement tumor biospecimens
obtained from melanoma patients before, during, and/or after anti-PD-1 therapy, to examine whether
expression of melanoma-PD-1 signaling effectors correlates with clinical outcome. These studies will enhance
our basic understanding of the mechanisms underlying melanoma progression and provide insight into how
melanoma-PD-1 signaling interactions may be effectively manipulated for improved tumor therapy.

## Key facts

- **NIH application ID:** 10222585
- **Project number:** 5R01CA190838-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Tobias Schatton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,502
- **Award type:** 5
- **Project period:** 2017-09-13 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222585

## Citation

> US National Institutes of Health, RePORTER application 10222585, Role of melanoma-PD-1 in cancer progression (5R01CA190838-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10222585. Licensed CC0.

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