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Investigating the impact of radiation therapy on oral squamous cell carcinoma microenvironment via non-classical class I major histocompatibility complex HLA-E

Award Number: F31DE035360
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Investigating the impact of radiation therapy on oral squamous cell carcinoma microenvironment via non-classical class I major histocompatibility complex HLA-E - Abstract. Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Resectable, locally advanced OSCC is approved to be treated with immune checkpoint inhibition (ICI) in combination with radiation therapy (RT) though responses are limited to a minority of patients. The goal of this proposal is to identify mechanisms of response and resistance to RT/ICI and test a therapeutic intervention to increase RT/ICI response in OSCC. In preliminary studies, we conducted analysis of several public databases including single cell RNA sequencing and bulk RNA sequencing of OSCC tumors, revealing that OSCCs are highly infiltrated by CD8+ T cells and NK cells that express the inhibitory receptor NKG2A. NKG2A, along with its ligand major histocompatibility complex E (MHC-E), serves as an important immune checkpoint preventing immune activation and cancer cell killing. To investigate this checkpoint in pre-clinical models, our lab has developed mouse SCC lines that can be implanted into the oral cavity of immune-competent mice. We previously identified mouse SCC lines of “responder” and “non-responder” to RT/ICI combination therapy. We observed that RT upregulated expression of MHC-E, which typically binds NKG2A by presenting a short, invariant “signal peptide”. RT-induced MHC-E expression was greater in the responder than in the non-responder. In the literature, researchers have found that non-signal peptides can replace signal peptides on MHC-E, preventing NKG2A binding, and suggest this may occur after RT. Together with my preliminary data, these findings suggest RT-induced MHC-E might not be immune-suppressive in the responder OSCC model after RT because of non-signal peptide presentation. Therefore, I hypothesize that RT-induced MHC-E non-signal peptide presentation promotes CD8+ T cell and NK cell activation against OSCC. To test this hypothesis, I propose the following aims. Aim 1: Determine the impact of RT-induced MHC-E on anti-tumor immune cells in OSCC. I will test whether NKG2A blockade in RT- treated OSCC cells alters NK and CD8+ T cell responses in vitro using co-culture models. I will also determine whether RT-induced MHC-E presents signal or non-signal peptide by mass spectrometry and cell-based ELISA. Overall, this aim will characterize the role of RT-induced MHC-E in the modulating the OSCC immune microenvironment. Aim 2: Test if NKG2A blockade can convert non-responders of RT/ICI therapy to responders. I will test combinations of RT, anti-PD-L1, and anti-NKG2A therapies for treating responder and non-responder OSCCs in vivo. In addition to assessing tumor volume and mouse survival, I will assess the impact of treatment on immune phenotypes by flow cytometry, single cell RNA sequencing, and spatial transcriptomics. Overall, this aim will test whether anti-NKG2A therapy in combination with RT/ICI can lead to durable immune responses against OSCC. Impact: These experiments will reveal novel mechanisms by which RT modulates the OSCC microenvironment and test a new therapeutic strategy to improve the treatment outcome of OSCC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $43,748 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Oral Diseases and Disorders Research	001	1	9/2/2026	NEW	$0
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Oral Diseases and Disorders Research	000	1	9/2/2026	NEW	$43,748
														Subtotal = $43,748

Grand Total All Awards = $43,748

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Investigating the impact of radiation therapy on oral squamous cell carcinoma microenvironment via non-classical class I major histocompatibility complex HLA-E

Award Number: F31DE035360

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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