# Targeting Unique Myeloid Populations to Overcome Anti-PD-1 Resistance Conferred by Specific Cancer Mutations

> **NIH NIH K08** · HARVARD MEDICAL SCHOOL · 2020 · $194,590

## Abstract

PROJECT SUMMARY
Research: Therapeutic resistance limits the efficacy of anti-PD-1 therapy for cancer: only 40% of melanoma
patients respond to this therapy, and half of these will develop resistance. Resistance can arise from several
mechanisms including mutations acquired by cancer cells or infiltration of tumors by immunosuppressive immune
cells. There is a critical need to understand resistance mechanisms to develop novel immunotherapeutic
strategies to overcome them. Based on our preliminary data, we hypothesize that cancer cells with resistance
mutations recruit unique immunosuppressive myeloid populations that can be targeted to overcome resistance
to anti-PD-1. To test this hypothesis, in Aim 1 we will determine how clinically-defined resistance mutations
impact immunosuppressive myeloid populations in mouse models using single-cell RNA-sequencing and in
human melanoma biopsies using multiplex immunofluorescence. In Aim 2 we will determine how inhibition of
myeloid cells can overcome resistance to anti-PD-1 with mechanistic mouse studies. This research will define
how to personalize immunotherapy based on a patient’s unique cancer mutations and infiltrating
immunosuppressive myeloid cells, with the long-term goal to improve responses to immunotherapy.
Candidate and Mentorship: The PI, Brian Miller, MD PhD, is an oncologist and cancer immunologist at the
Dana-Farber Cancer Institute and Harvard Medical School. He spends 90% of his time in translational research
and 10% in clinical practice caring for patients with cancer. His goal is to lead an independent academic research
laboratory studying the functions of myeloid cells in the tumor microenvironment and developing therapeutic
strategies to overcome resistance to immunotherapy. He will pursue this goal by: 1) developing expertise in the
generation and analysis of single-cell RNA-sequencing data; 2) becoming an expert in myeloid cell biology and
developing in vitro and in vivo functional assays; 3) establishing a community of mentors and collaborators; 4)
completing coursework to expand his computational and statistical background. He will be mentored by Dr.
Arlene Sharpe, an expert in tumor immunology, along with a strong scientific advisory committee with expertise
in computational biology, myeloid cells, and translational immunotherapy: Dr. Peter Kharchenko, Dr. Jon Kagan,
and Dr. Stephen Hodi. These mentors and his career development plan will help him acquire the skills and
expertise needed to develop his own distinct niche in single-cell analysis of the tumor microenvironment and
functional dissection of tumor-infiltrating myeloid cells.
Environment: Dr. Miller will conduct this research at Harvard Medical School and leverage the exceptional
research and teaching environment at Harvard, the Dana-Farber Cancer Institute, and the Broad Institute. In
addition, his network of collaborators at the Dana-Farber Cancer Institute, Broad Institute, and Bristol-Myers
Squibb will provide reagen...

## Key facts

- **NIH application ID:** 9953289
- **Project number:** 1K08CA248960-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Brian C Miller
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,590
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953289

## Citation

> US National Institutes of Health, RePORTER application 9953289, Targeting Unique Myeloid Populations to Overcome Anti-PD-1 Resistance Conferred by Specific Cancer Mutations (1K08CA248960-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953289. Licensed CC0.

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