# Coordinating tumor differentiation and immune suppression with the metabolic state and treatment outcome

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $33,932

## Abstract

SUMMARY
Therapeutic immune checkpoint blocking antibodies and oncogene-targeted chemical inhibitors have
revolutionized the treatment landscape for cancers, and now provide real hope to patients with advanced
disease. However, while some patients will experience benefit, others will not respond at all – a dilemma
that is intimately linked to the genetic composition of the tumors. Identification of the molecular processes
that enable, as well as preclude, positive responses to such therapies are urgently needed, and are likely to
identify rational combinatorial approaches that will improve outcome. For immune checkpoint inhibitor
therapies, evidence has accumulated to suggest that the mutational burden in the patients' cancer, through
an increased frequency of neoantigen peptides, causes immunogenicity. In order to grow, such antigenic
tumors must develop mechanisms that enable them to evade immune-mediated destruction, which makes
these tumors vulnerable to immune checkpoint therapies that reverses tumor immune evasion. From our
ongoing studies on how melanoma cells elude the efficacy of oncogene-targeted therapies, we have
identified an immunosuppressive molecule whose expression levels are directly linked to the tumors
metabolic state. While oncogene-targeted therapies tend to cause an increased expression of melanoma
antigens, which is triggered by altered metabolic demands and MITF-mediated regulation of mitochondrial
biogenesis through PGC1there is a drastic decrease in the levels of this immune suppressive molecule.
Hence, these data suggested that increased immune surveillance may intersect with the effects of targeted
therapies. Our preliminary studies demonstrate that oncogenic signaling governs transcriptional regulation
of transcriptional regulation of this immune suppressive molecule, and that manipulation of its levels alters
tumor growth in vivo, associated with changes in tumor immunogenicity. Furthermore, we demonstrate that
heightened expression of this molecule is correlated with poor prognosis in patients who otherwise would be
expected to benefit from immune checkpoint therapies. In this proposal, we will perform studies that dissect
the molecular mechanisms that control this immune suppressive molecule's expression levels. We will
further assess the degree to which this protein modifies the effects of immune checkpoint therapies, and
determine if its prospective use might be used to inform clinical decisions. Successful completion of the
proposed studies should improve clinical management and propose combinatorial targets for investigation.

## Key facts

- **NIH application ID:** 10090455
- **Project number:** 5R01CA207982-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Hans Ragnar WIDLUND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,932
- **Award type:** 5
- **Project period:** 2017-01-17 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090455

## Citation

> US National Institutes of Health, RePORTER application 10090455, Coordinating tumor differentiation and immune suppression with the metabolic state and treatment outcome (5R01CA207982-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10090455. Licensed CC0.

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