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Targeting Endogenous Retrovirus Regulation for Augmenting Cancer Immunotherapy

Award Number: K00CA253767
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Targeting Endogenous Retrovirus Regulation for Augmenting Cancer Immunotherapy - PROJECT SUMMARY Immune-modulating therapies have been revolutionary treatments for several cancer types including melanoma, lung cancer, and renal cell carcinoma. However, most cancer patients do not respond to immunotherapies, and there remains a critical need to identify alternative approaches to treating these cancers. Endogenous retroviruses (ERVs) are genetic remnants of retroviral infection transmitted vertically through generations, whose transcription can result in type-I interferon activation, and/or presentation of ERV-associated antigens. Recent studies on ERVs in human cancer has shown that ERV expression can render cells immunogenic in a variety of cancer types including colorectal, breast cancer and melanoma. Therefore, characterization of how ERV expression is regulated in cancer will reveal opportunities to therapeutically de-repress ERVs and improve immunotherapy outcomes in low antigen tumors. In the F99-phase of this proposal, I will investigate the role of epigenetic factors regulating ERV expression and anti-tumor immunity in melanoma. Specifically, I will test melanoma tumors for ERV tetramer-positive CD8+ T cells, to determine the antigenicity of de-repressed melanoma ERVs. Furthermore, I will determine the mechanism by which type-I interferon response is induced in epigenetically-modified tumors, and determine the role of ERV MHC-I antigens through genetic knockouts of each component and evaluating tumor growth and immunogenicity. This work will establish the mechanism by which ERVs are regulated epigenetically, and establish a framework for investigating ERV regulation and its impact on the immune response to cancer. In the K00-phase of this proposal, I will harness my experience studying ERVs to investigate their utility in improving the immune response to antigen-low tumor types. Specifically, I will perform a CRISPR screen to identify druggable regulators of HERV expression in human cancer cell lines. I will then validate these candidate regulators by pharmacologically targeting them and testing the induction of type-I interferon and antigenic responses in these cells. Finally, I will evaluate whether ERV-specific CAR-T cells can react to ERV-induced cells in vivo. This proposed research will clarify the mechanisms by which ERVs are epigenetically regulated in cancer, and identify novel and actionable targets for re-expressing ERVs in difficult-to-treat tumor types. This will lead to improved immunotherapeutic strategies for treating cancers with poor patient outcomes.


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 = $107,050 )
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	6	4/18/2025	NON-COMPETING CONTINUATION	$107,050
														Subtotal = $107,050

Issue Date FY: 2024 ( Subtotal = $107,050 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	5/21/2024	NON-COMPETING CONTINUATION	$99,264
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	5	7/22/2024	NON-COMPETING CONTINUATION	$7,786
														Subtotal = $107,050

Issue Date FY: 2023 ( Subtotal = $94,506 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	4	5/11/2023	NON-COMPETING CONTINUATION	$94,506
														Subtotal = $94,506

Issue Date FY: 2022 ( Subtotal = $91,368 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	3	6/6/2022	EXTENSION WITH OR WITHOUT FUNDS	$91,368
														Subtotal = $91,368

Grand Total All Awards = $399,974

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Targeting Endogenous Retrovirus Regulation for Augmenting Cancer Immunotherapy

Award Number: K00CA253767

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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