# Dissecting the genetic basis of cancer immune evasion in squamous cell carcinoma

> **NIH NIH F99** · UNIVERSITY OF CHICAGO · 2024 · $50,474

## Abstract

PROJECT SUMMARY/ABSTRACT
While immunotherapies have revolutionized cancer treatment, a subset of patients, particularly those with
squamous cell carcinomas (SCCs) found in the skin, oral cavity, larynx, esophagus, lung, and cervix, exhibit
varying responses to immune checkpoint blockade (ICB), resulting in a 60% relapse rate. These disparities in
patient outcomes strongly suggest the existence of genetic variations that underlie their distinct responses to
ICB. Although the specific oncogenic mutations responsible for driving relapse in SCC patients remain unclear,
it is imperative to grasp the mechanisms of cancer immune evasion in individuals with specific genetic profiles
to enhance the precision of immunotherapy. Recent research has identified a population of tumor-initiating cells
(TICs) within skin and oral cavity SCCs that resist anti-tumor immunity and drive relapse. These rare TICs are
often overlooked in tumor immunology studies despite their critical role in promoting cancer recurrence. We have
identified that activating mutations in the PIK3CA gene, found in 20% of cutaneous and head and neck SCCs,
can enhance stemness and intrinsic immune resistance in SCCs, resulting in rapid relapse after ICB. The
proposed research will consist of two main aims. The F99 phase aims to determine how PIK3CA mutations
expand the immune-resistant TICs in SCC tumors. I will investigate whether PIK3CA activating mutations induce
TIC self-renewal and dedifferentiation following ICB treatment. I will explore the role PIK3CA mutants have on
the Sox2 protein, a critical transcription factor for maintaining stemness, and its stability in TICs. This aim will
provide insights into the ability to disrupt PIK3CA mutant-induced Sox2 stability to reduce SCC relapse after
immunotherapy. The K00 phase is broader with the goal of identifying how genetic alterations enhance the
intrinsic immune resistance of TICs. In the first part of the K00 phase, I will design a genome-wide CRISPR
screen to identify candidate genes responsible for endowing PIK3CA mutant TICs with resistance to T cell-
mediated ferroptosis. I will explore how PIK3CA mutations reprogram the metabolism of TICs to enhance their
intrinsic resistance to T cell-induced ferroptosis. I will then expand the scope to identify other genetic
determinants beyond PIK3CA mutations that drive immune evasion in TICs. By CRISPR gene editing, I will
introduce other oncogene activation, tumor suppressor inactivation, chromosomal rearrangements, gene
fusions, and copy number variations into keratinocytes and evaluate their potential to promote immune evasion
in vivo. This work will discover potential drug targets and biomarkers for predicting patient responses to
immunotherapy. My ultimate goal is to become an independent investigator at a leading research institution and
to conduct interdisciplinary, NIH-funded research contributing to the fields of cancer biology, stem cell biology,
and immunology, and by characterizing...

## Key facts

- **NIH application ID:** 10990206
- **Project number:** 1F99CA294257-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Benjamin Nicholson
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $50,474
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990206

## Citation

> US National Institutes of Health, RePORTER application 10990206, Dissecting the genetic basis of cancer immune evasion in squamous cell carcinoma (1F99CA294257-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10990206. Licensed CC0.

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