# Target metabolic vulnerabilities of MDSCs to enhance cancer immunotherapy

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $171,932

## Abstract

Summary 
 
MDSCs are one of the major types of immune cells that contribute to tumor-­induced immune suppression and 
escape  from  immune  elimination.  Importantly,  MDSCs  have  been  suggested  to  contribute  to  resistance  to 
various cancer therapies, including to anti-­CTLA-­4 and anti-­PD-­1 blockade.  Hence, targeting MDSCs could be 
an attractive approach to modulate tumor immunity to improve current cancer immunotherapies. We have very 
recently  reported  that  phenformin,  a  mitochondrial  respiratory  chain  complex  I  inhibitor,  selectively  reduced 
proportion of polymorphonuclear MDSCs (PMN-­MDSCs), but not other immune cells in spleens of tumor-­bearing 
mice. Phenformin also inhibited proliferation of PMN-­MDSCs derived from bone marrow co-­cultured with tumor 
cells  in  vitro.  Furthermore,  PMN-­MDSCs  derived  from  mice  treated  with  phenformin  showed  attenuated 
suppressive  activities  towards  CD8+  T  cells  in  T  cell  proliferation  assays.  In  our  unpublished  metabolomics 
profiling  studies  of  PMN-­MDSCs,  we  have  uncovered  additional  potential  metabolic  vulnerabilities  of  PMN-­
MDSCs. Based on these findings, we hypothesize that PMN-­MDSCs possess distinguishing metabolic features.  
Given the important contribution of MDSCs to tumor immune escape and immunotherapy resistance, we further 
hypothesize that targeting the metabolic vulnerabilities of PMN-­MDSCs may cooperate with immune checkpoint 
blockade to unleash T cell responses, leading to improved anti-­tumor efficacy. In aim 1, we plan to characterize 
the metabolic vulnerabilities of PMN-­MDSCs. We will not only elucidate metabolic features of PMN-­MDSCs that 
underlie their sensitivity to phenformin, but also identify other metabolic targets of PMN-­MDSCs, such as those 
involved in the glutamine metabolism. In aim 2, we will assess the therapeutic benefit of combining targeting the 
metabolic  vulnerabilities  of  PMN-­MDSCs  with  immune  checkpoint  blockade  in  mouse  cancer  models.  We  will 
evaluate the effects of metabolic drugs in combination with anti-­PD-­1 blockade, on the tumor microenvironment 
and analyze the contribution of PMN-­MDSC modulatory activity of these metabolic drugs using the PMN-­MDSC 
adoptive transfer approach.

## Key facts

- **NIH application ID:** 9834838
- **Project number:** 5R21CA227588-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Bin Zheng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,932
- **Award type:** 5
- **Project period:** 2018-12-10 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834838

## Citation

> US National Institutes of Health, RePORTER application 9834838, Target metabolic vulnerabilities of MDSCs to enhance cancer immunotherapy (5R21CA227588-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9834838. Licensed CC0.

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