# CD73 expression on cancer-associated fibroblasts of Head and Neck Cancers shapes the immune landscape

> **NIH NIH R21** · AUGUSTA UNIVERSITY · 2020 · $192,187

## Abstract

Head and Neck squamous cell carcinomas (HNSCCs) are highly aggressive multi-factorial diseases affecting
600,000 patients worldwide each year. Alcohol, tobacco, and HPV exposure are known causative factors for
HNSCCs, but HPV- HNSCCs represent about 80% of the incidence and are associated with poor clinical
outcomes, especially those that manifest a mesenchymal phenotype. Despite the major advances of PD-1/PD-
L1 and CTLA-4 checkpoint inhibitors in providing curative benefits for some cancer patients, the response rate
in HNSCC patients to these checkpoint inhibitors is limited. Besides the high levels of heterogeneity and immune
cell plasticity, a highly immunosuppressive tumor microenvironment (TME) is another contributing factor to the
poor clinical outcomes of HNSCCs, which underscores the need for defining additional immune checkpoints non-
redundant to the PD-1/PD-L1 pathways. CD73 is a major ecto-5'-nucleotidase and a rate limiting enzyme that
converts the immune stimulatory ATP to adenosine (ADO), which inhibits T cell activation and induces apoptosis.
Thus, CD73 serves as a prevalent immune checkpoint for maintaining immunosuppression. Clinically, high CD73
expression in total HNSCC tissues has been implicated in poor prognoses. Nevertheless the major contributor
of CD73 activity in the HNSCC tumor microenvironment (TME) has not been identified and should be addressed
by rigorous and comparative examination of each cell type because the observed elevated CD73 expression in
total tumor tissues could be a result of either an increase in CD73 levels in one cellular subtype or an increase
in the frequency of this cell type. Recently, we observed that cancer-associated fibroblasts (CAFs), the prominent
non-hematopoietic stroma in the TME, expressed the highest levels of CD73, whereas CD73 expression was
highly variable in other cellular constituents of the HNSCC TME. Furthermore, immune cell plasticity in HNSCCs,
including the loss of T cells in the TME, was associated with high CAF abundancy and high CAF-CD73 levels.
Given the highly heterogeneous cellular constituents of HNSCCs, we propose that a comprehensive comparative
analysis of CD73 expression in different cell types in the context of their relative abundancy and bio-distribution
will provide more insight into the major contributor(s) of the total CD73 activity and the effects of CAF abundancy
to immune cell plasticity. Using fresh HNSCC specimens and state-of-the-art technical approaches, we will
address the crucial questions of whether and how CAF-CD73 modulates immune cell plasticity with two specific
aims: (1) to define and correlate the CD73 expression levels on CAFs with immune cell plasticity via FACs and
multiplexed IHC; and (2) to demonstrate the plasticity of CAFs and immune cells in the HNSCC TME via
transcriptome profiling of purified tumors, CAFs, and TILs from typical HNSCCs and mesenchymal-like HNSCCs,
as well as to demonstrate their differential CD73 enzymatic activity...

## Key facts

- **NIH application ID:** 9912757
- **Project number:** 5R21DE028716-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** YAN CUI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,187
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912757

## Citation

> US National Institutes of Health, RePORTER application 9912757, CD73 expression on cancer-associated fibroblasts of Head and Neck Cancers shapes the immune landscape (5R21DE028716-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9912757. Licensed CC0.

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