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Immune receptor degradation for immune evasion of head and neck cancer

Award Number: R01DE033797
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: 06/10/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Immune receptor degradation for immune evasion of head and neck cancer - PROJECT SUMMARY Human papillomaviruses (HPVs) cause 5% of all human cancers, including most cervical cancers and approximately 25% of head and neck squamous cell carcinomas (HNSCCs). The alarming rise in cases of HPV- positive (HPV+) HNSCCs has been observed over the past few decades. Despite this, our understanding of the precise mechanisms underlying HPV-driven disease progression, particularly concerning the host immune response, remains limited. Current immunotherapies with immune checkpoint inhibitors (ICIs) reactivate exhausted T cells. However, in cancers like HPV+ HNSCC, downregulation of major histocompatibility complex class I (MHCI) and costimulatory molecules hampers T-cell responses. The mechanisms behind this downregulation are largely unknown. HPV+ HNSCC patients consistently show low MHCI and costimulatory receptors on tumor cells, contributing to poor response rates in ICI therapy. Membrane-associated RING-CH finger 8 (MARCHF8), homologous to Kaposi’s sarcoma herpesvirus K3 and K5, downregulates MHCI through ubiquitination. Our study revealed that HPV activates MARCHF8, promoting MHCI degradation. Knocking out MARCHF8 in HPV+ HNSCC cells increased the expression of multiple immune receptors, including MHCI, improved mouse survival, and enhanced NK and T cell infiltration. Notably, we also identified that the MARCHF8-mediated ubiquitination of MHCI triggers its degradation via selective autophagy. Based on these compelling results, we propose that the MARCHF8- autophagy axis plays a crucial role in promoting cancer progression by evading T-cell responses. This indicates that targeting the MARCHF8-autophagy pathway could offer a promising therapeutic strategy for novel immunotherapies to treat HPV+ HNSCC. In this project, we will 1) determine if targeting MARCHF8 activates antitumor immunity by remodeling the tumor microenvironment of HPV+ HNSCC; 2) determine the mechanisms by which MARCHF8 ubiquitinates and degrades MHCI proteins; and 3) develop novel immunotherapies by targeting the MARCHF8-autophagy pathway. Current immunotherapies using ICIs have limited success, with over 70% of patients not responding. ICI- refractory cancers show low MHCI expression and T-cell infiltration. Targeting MARCHF8 and autophagy could restore immune receptors and offer new treatment options for non-responders with HNSCC.


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 = $633,851 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Oral Diseases and Disorders Research	000	2	3/30/2026	NON-COMPETING CONTINUATION	$633,851
														Subtotal = $633,851

Issue Date FY: 2025 ( Subtotal = $642,488 )
2025	2025	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Oral Diseases and Disorders Research	000	1	6/10/2025	NEW	$642,488
														Subtotal = $642,488

Grand Total All Awards = $1,276,339

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Immune receptor degradation for immune evasion of head and neck cancer

Award Number: R01DE033797

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: 06/10/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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