# Evolutionary Trajectories of Tumors Following Resistance to Immune Checkpoint Blockade

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $133,668

## Abstract

PROJECT SUMMARY
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but the majority of patients who
receive ICB develop resistance and ultimately need to be treated with multiple therapies. Mapping the
expected patterns of evolution has enabled rational sequencing of treatments for many cancer therapies,
particularly targeted therapies. However, we currently have a limited understanding of how treatment with ICB
shapes the evolutionary trajectory of a tumor. Most cancer therapies kill tumor cells directly and leave behind a
small remnant of cell-intrinsically drug-resistant tumor cells; from an evolutionary perspective, this results in a
clonal sweep after treatment in which drug-resistant cells take over the tumor. In contrast, ICB acts by
mobilizing a patient’s own immune cells, particularly T cells, against the tumor, and tumors frequently develop
resistance to ICB by establishing a “cold” tumor microenvironment that is inhospitable to T cells. In cases
where ICB resistance is mediated by the entire tumor microenvironment, it is not clear that resistance will be
accompanied by such a clonal sweep; rather, it raises the question as to whether tumor cells which would be
sensitive to ICB on their own might be protected if they reside alongside neighbors that can create a sufficiently
“cold” microenvironment. In support of this, a study of melanoma patients has suggested that an evolutionary
pattern of clonal persistence—in which many tumor populations survive therapy—is found in many ICB-
resistant tumors. In this proposal, we will seek to map out the evolutionary trajectories of tumors after ICB in
both a mouse model of squamous cell carcinoma and in bladder cancer patients. We will in particular seek to
test the hypothesis that clonal persistence is dominant pattern of evolution following ICB, particularly in tumors
which exhibit a “cold” microenvironment. We have established a novel mouse model system in which we can
track multiple tumor populations in the same tumor—e.g., an “immune hot” and an “immune cold” population—
via fluorescent tags. We will use this model to interrogate whether the presence of an “immune cold” tumor
population that drives a “cold” microenvironment can protect otherwise-sensitive “immune hot” tumor cells from
ICB-mediated clearance. Such protection by a “cold” tumor population would establish a mechanistic link
between a “cold” microenvironment and an evolutionary pattern of clonal persistence. We will complement
these studies with genomic analysis of tumors that have been treated with ICB, investigating both mouse
squamous skin carcinomas treated with a-PD-1/a-TGFb combination therapy and patient bladder tumors
treated with a-PD-L1. By constructing a detailed picture of pre- and post-ICB tumor clonal architecture across
these two cohorts, we will map the evolutionary trajectories of ICB-treated tumors and determine whether a
pattern of clonal persistence is associated with ICB resistance and specif...

## Key facts

- **NIH application ID:** 10559077
- **Project number:** 7R21CA264599-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Melissa Quino Reeves
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $133,668
- **Award type:** 7
- **Project period:** 2021-07-05 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10559077

## Citation

> US National Institutes of Health, RePORTER application 10559077, Evolutionary Trajectories of Tumors Following Resistance to Immune Checkpoint Blockade (7R21CA264599-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10559077. Licensed CC0.

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