# Overcoming Tumor-Intrinsic Therapeutic Resistance to Immunotherapies

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $204,106

## Abstract

PROJECT SUMMARY/ABSTRACT
Immune checkpoint blockers (ICBs) such as anti-CTLA-4 and anti-PD-1 are revolutionizing the field of cancer
care, emerging as the fourth pillar of cancer therapies. To date, more than 60 approvals of utilizing ICBs to treat
various types of cancer have been granted by the FDA. Despite their transformative response, the overall efficacy
of ICBs is limited to a small subset of cancer patients, because of therapeutic resistance. We and others recently
found that loss of IFN- signaling genes in advanced melanoma and colon cancer is a major mechanism of
resistance to ICBs. Therefore, identifying therapeutic strategies capable of overcoming this resistance is of
utmost importance. Based on our preliminary data, we hypothesize that deletion of IFN- signaling in tumor cells
(IFNR1KO) augments the Myc-glutaminolysis pathway and metabolically forges an “immune-cold” tumor
microenvironment, conferring therapeutic resistance to ICBs. In Aim 1, we will determine metabolic mechanisms
by which the IFNR1-Myc axis regulates therapeutic response to ICBs in both mouse and human melanoma. In
Aim 2, we will dissect cellular mechanisms by which the IFNR1-Myc axis mediates ICB resistance, and attempt
to target Myc-driven metabolic pathways to overcome ICB resistance. We will also test these metabolic
modulators as potential effective strategies to sensitize “immune cold” IFNR1KO tumors to ICBs. While metabolic
reprogramming in tumor cells has been correlated with therapeutic resistance to chemotherapies, to the best of
our knowledge, there is no prior study directly linking metabolic reprogramming to therapeutic resistance to ICBs.
As such, we predict insights gained from our studies will significantly advance our understanding of how
metabolic reprograming associated with tumor-intrinsic alterations coordinates therapeutic responses of ICBs.
These studies may manifest “targeted” therapies for cancer patients who are resistant to ICBs.

## Key facts

- **NIH application ID:** 10531909
- **Project number:** 5R21CA259721-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Lewis Z. Shi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $204,106
- **Award type:** 5
- **Project period:** 2021-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531909

## Citation

> US National Institutes of Health, RePORTER application 10531909, Overcoming Tumor-Intrinsic Therapeutic Resistance to Immunotherapies (5R21CA259721-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10531909. Licensed CC0.

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