# Elucidating Mechanism of Immune Evasion in Head and Neck Cancers

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $535,210

## Abstract

Project Summary/Abstract
 It is crucial to better understand immune evasion mechanisms in head and neck cancers in order to
enhance their susceptibility to immunotherapy. About 90% of head and neck cancers are squamous cell
carcinomas (HNSCC). Recurrent or metastatic HNSCCs are being treated with checkpoint blockade
immunotherapy targeting programmed death 1 (PD-1), a co-inhibitory receptor on T cells. However, only a
subset of HNSCC patients responded to such anti-PD-1 therapy (10-20%). Thus, there is an urgent need to
elucidate mechanisms underlying therapy unresponsiveness to single blockade of PD-1. Apart from PD-1, T
cells express other co-inhibitory receptors that can also induce immunosuppressive phenotypes, such as
lymphocyte activation gene-3 (LAG-3). However, the role of such receptors remains poorly defined in immune
evasion of HNSCCs (e.g., LAG-3). Our preliminary data show that HNSCC patients exhibit a highly
heterogeneous pattern of tumor infiltrating lymphocytes (TILs); however, the molecular drivers underlying such
differential immune phenotypes remain largely unknown. Completion of our proposed studies may generate
novel insight into the mechanisms that determine the success or failure of checkpoint blockade
immunotherapy. We expect our studies to delineate the comprehensive immune landscape of HNSCCs in
human patients. The knowledge gained would provide critical steps toward improving immunotherapy by
targeting additional co-inhibitory receptors with a more rational design and overcoming the dysfunctional
progression of TILs.
 Our long-term goal is to elucidate immune evasion mechanism and improve therapeutic strategies of
HNSCCs. HNSCC development often associates with oncogenic mutations, such as heterozygous loss of
Smad4, gain-of-function mutations of PIK3CA or loss-of-function mutations of Notch1. It remains largely
unknown how HNSCCs evade immune recognition. To address this question, we performed studies with a
transplanted SCC model caused by combining KrasG12D mutation and Smad4 loss (termed KRS-SCC). We
found that KRS-SCC tumors completely escaped T cell-mediated anti-tumor responses, manifested with
exhausted CD8 and CD4 TILs co-expressing PD-1 and LAG-3. Consistently, dual inhibition of PD-1 and LAG-3
suppressed the growth of KRS-SCCs. We propose to employ our unique mouse models and human patient
samples to further elucidate immune evasion mechanisms of HNSCCs. Our proposed studies may
substantially advance our understanding in mechanisms that underlie therapy failure of single PD-1 blockade.
Relevance to public health. We envision that our studies will provide substantial advances in understanding
the mechanisms that underlie therapy failure of PD-1 blockade in HNSCCs. We anticipate that our proposed
studies will reveal the connection between intrinsic characteristics of tumor cells and immune signature of TILs.
These studies not only address fundamental questions in cancer immunology but also lay a scientific
foun...

## Key facts

- **NIH application ID:** 10489307
- **Project number:** 5R01DE027329-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jing Hong Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $535,210
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489307

## Citation

> US National Institutes of Health, RePORTER application 10489307, Elucidating Mechanism of Immune Evasion in Head and Neck Cancers (5R01DE027329-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489307. Licensed CC0.

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