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Immune determinants of progression from Oral Epithelial Dysplasia to Oral Squamous Cell Carcinoma by precision multiplexed imaging

Award Number: R01DE032033
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Immune determinants of progression from Oral Epithelial Dysplasia to Oral Squamous Cell Carcinoma by precision multiplexed imaging - PROJECT SUMMARY/ABSTRACT Oral and oropharyngeal cancers result in over 10,000 deaths each year in the United States. Although oral squamous cell carcinoma (OSCC) patients with localized disease have survival rates of up to 80%, about two-thirds present clinically with regional and distant metastases associated with five-year survival rates of 50% and 35%, respectively. Despite advances in immunotherapy, the five-year mortality rate for OSCC has remained constant over the last several decades, underscoring the importance of early detection and intervention. The majority of OSCCs arise from pre-cancerous lesions called oral epithelial dysplasias (OED), only some of which will progress to invasive cancers. Patients with OEDs that will progress would likely benefit from more aggressive treatment early on; however, the morbidities associated with aggressive treatment are significant, preventing their broad use in all patients. While this general outlook is similar across many cancers, the accessibility of oral cavity lesions also provides a unique opportunity for detailed analysis to understand the biological processes that contribute to or protect against progression into invasive and malignant cancer. We will test the hypothesis that the immune response to OED regulates the risk of progression. The immune system responds to disruptions and danger in tissues. Significant evidence supports the important role of the immune system in responding to early lesions in the oral cavity, including an abundance of immune cells infiltrating these tissues, elevated risk in immunosuppressed individuals, and loss of MHC class I antigen presentation machinery in many OSCC tumors. However, features of the immune response are not currently utilized to define treatment strategies or to stratify risk in OED or OSCC patients, presenting an unmet opportunity. The recent development of multiplexed ion beam imaging (MIBI) enables unprecedented detailed analysis of archival pathological tissues. This technology, which we recently implemented with the help of an NIH Instrumentation Grant, uses antibodies conjugated to heavy-metal reporter ions to quantify up to 50 proteins simultaneously at subcellular (400nm) resolution in formalin-fixed paraffin-embedded tissues. We have collated a substantial number of archival tissues from OED patients with detailed clinical and follow up data, including progression to OSCC. Here, we will leverage MIBI to conduct a detailed analysis of immune responses in these tumors, providing new insight into the immunological mechanisms and cellular interactions in these microenvironments. In Aim 1, we will test the hypothesis that the types of immune cells present and their activation states are distinct between OEDs that went on to progress versus those that have not. In Aim 2, we will test the hypothesis that the architecture and cellular neighborhoods within the tissue are distinct in OEDs that progressed to OSCC. In Aim 3, we will use these data to identify immune features associated with and predictive of risk of progression. These studies will harness a new imaging technique to answer fundamental questions about the immune response and to guide precise treatment decisions for patients with OED.


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: 2025 ( Subtotal = $738,039 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	4	5/7/2025	NON-COMPETING CONTINUATION	$73,803
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	4	3/11/2025	NON-COMPETING CONTINUATION	$664,236
														Subtotal = $738,039

Issue Date FY: 2024 ( Subtotal = $723,279 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	3	6/18/2024	NON-COMPETING CONTINUATION	$59,043
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	3	3/20/2024	NON-COMPETING CONTINUATION	$664,236
														Subtotal = $723,279

Issue Date FY: 2023 ( Subtotal = $870,934 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	002	2	3/8/2023	SUPPLEMENT FOR EXPANSION	$135,964
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	003	2	6/27/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	2	3/7/2023	NON-COMPETING CONTINUATION	$734,970
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	10/18/2022	NEW	$0
														Subtotal = $870,934

Issue Date FY: 2022 ( Subtotal = $749,410 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	6/15/2022	NEW	$749,410
														Subtotal = $749,410

Grand Total All Awards = $3,081,662

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Immune determinants of progression from Oral Epithelial Dysplasia to Oral Squamous Cell Carcinoma by precision multiplexed imaging

Award Number: R01DE032033

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/15/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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