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Deciphering the Immune Evasion Mechanisms in Mutant IDH1 Cancer

Award Number: K22CA288784
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Deciphering the Immune Evasion Mechanisms in Mutant IDH1 Cancer - Project Summary Mutations in isocitrate dehydrogenase 1 (mIDH1) are prevalent in various solid tumors, including intrahepatic cholangiocarcinoma (ICC), leading to the production of (R)-2-hydroxyglutarate (2HG). This oncometabolite disrupts epigenetic and metabolic processes by inhibiting enzymes involved in DNA demethylation. I have developed a genetically engineered mouse model (GEMM) that recapitulates the genetics and histopathologic features of human mIDH1 ICC. I revealed that mIDH1 creates an immunosuppressive microenvironment in ICC centered on dual 2HG-mediated mechanisms suppressing CD8+ T cell anti-tumor activity. These properties are reversed by mIDH1 inhibition leading to reduced tumor growth associated with pronounced activation of immune stimulatory interferon (IFN) signaling and CD8+ T cell recruitment and effector function. My progress reveals that restoring antitumor immunity is central to mIDH1 inhibitor efficacy. However, we still have an incomplete understanding of the basis of mIDH1-mediated immune evasion that must be addressed to advance my mechanistic understanding and guide therapeutic development. My preliminary data suggest that mIDH1 ICCs are 'immunologically cold' due to two distinct mechanisms: a tumor cell-intrinsic pathway that hampers immunological recognition of the tumor cells and a paracrine program that curbs immune cell function. i) mIDH1 suppresses innate immunity: My research shows mIDH1 suppresses innate immunity, as evidenced by a low type I IFN gene signature and silencing of the cGAS sensor. Conversely, AG120 rapidly induces endogenous retrovirus (ERV) expression. Notably, cGAS and ERV-derived reverse transcriptase deletion blocks AG120 efficacy. ii) Metabolic crosstalk: My recent studies show that mIDH1 also impairs immune cell function via metabolic crosstalk by affecting T cell effector function and macrophage polarization. My preliminary studies suggest that these effects are due, in part, to the uptake of tumor-derived 2HG by these immune lineages as well as by metabolic cross-competition, with mIDH1 driving high levels of glycolysis, potentially limiting nutrient availability required for immune cell function. I aim to test whether these two processes collectively cause the immune suppressive phenotype of mIDH1 tumors. This study will elucidate the biology of this oncogene, and my data indicate that mIDH1 gliomas share common themes, suggesting a broader impact. I will focus on three specific aims: 1) Decipher the role of viral mimicry in response to mIDH1 inhibition; 2) Explore the contribution of metabolic crosstalk to immune evasion. These studies will offer novel insights into the mechanisms of mIDH1 inhibition in cancers, potentially leading to the development of more effective therapeutic strategies and enhancing understanding of tumor-immune communication. To support this work, I have outlined a career development plan to refine skills in laboratory management, knowledge dissemination, and securing independent funding. Securing a K22 award will be instrumental in achieving my long-term goal of becoming an independent researcher in cancer metabolism and immunology and will propel my pursuit of innovative cancer therapies.


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 = $196,029 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	2	4/19/2026	NON-COMPETING CONTINUATION	$196,029
														Subtotal = $196,029

Issue Date FY: 2025 ( Subtotal = $196,029 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Cancer Research Manpower	000	1	3/18/2025	NEW	$196,029
														Subtotal = $196,029

Grand Total All Awards = $392,058

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Deciphering the Immune Evasion Mechanisms in Mutant IDH1 Cancer

Award Number: K22CA288784

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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