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3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation

Award Number: R01CA244838
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation - PROJECT SUMMARY/ABSTRACT Malignant transformation (MT) of IDH-mutant low grade glioma (LGG) to aggressive high grade tumors is an event of major clinical significance, eventually leading to death in the majority of LGG patients. We discovered that mutations in IDH promote an immunosuppressed microenvironment characterized by decreased production of STAT1-regulated chemokines and low CD8+ T cell infiltration in LGG. In malignantly transformed tumors, we identified the unexpected deletion of the IDH1 mutant allele that may drive counteracting changes to the immunosuppressed microenvironment specifically during MT. LGG that undergo treatment-induced hypermutation (HM), another route to MT, produce more high quality neoantigens. Overall in malignantly transformed tumors relative to patient-matched LGG, we found increasing numbers of T cell clones and increasing expression of genes involved in cytotoxic T cell attraction and effector function. Based on these data, we hypothesize that immunosuppression in IDH mutant LGG is reduced upon MT, driven by genetic alterations that are acquired primarily during malignant transformation. To address this hypothesis, we will quantify spatial and temporal changes in mutant IDH1-driven immunosuppression during MT (Aim 1). We have devised a novel 3-dimensional (3-D), tumor-wide approach in which we will acquire 10 spatially mapped samples per tumor representing maximal anatomy of the tumor. The full cohort will include 30 malignantly tranformed and 30 non-malignantly transformed recurrences from patients for which we have banked samples of the matching initial IDH1-mutant LGG. We will use a high-sensitivity T cell repertoire assay, cytometry by Time of Flight (CyTOF), RNAseq based deconvolution, and multiplex immunohistochemistry to map the immunologic landscape in 3-D, and determine the extent to which mutant IDH1-mediated immunosuppression is reduced during MT. In Aim 2, we will determine how genetic alterations acquired during MT affect mutant IDH1-mediated immunosuppression. We will perform deep whole exome sequencing on samples collected in Aim 1 to map the intratumoral genomic landscape in 3-D during MT. We will test for the local influence of MT- associated genetic alterations, including high quality neoantigens in hypermutated tumors, deletion of the mutant IDH1 allele, or other genetic events on immunosuppression. Understanding which genetic events contribute to changes in immunosuppression is critical for selecting targeted therapies that could synergize with immunotherapies to prevent or delay MT. To begin to develop T cell based therapies, we will capture neoepitope-specific T cells, prioritizing those that are present tumor-wide, and determine the neoepitopes/HLAs they target and the amino acid sequences for corresponding T Cell Receptor (TCR) α- and β-chains. We will then test the cloned TCR for relative target specificity and activity against neoantigen- positive patient-specific tumor cells. The 3-D immuno-genomic landscapes across wide swaths of the tumor will be essential to the design of personalized therapies that have activity against the whole tumor.


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: 2024 ( Subtotal = $543,064 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	5	6/7/2024	NON-COMPETING CONTINUATION	$543,064
														Subtotal = $543,064

Issue Date FY: 2023 ( Subtotal = $560,211 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	4	6/30/2023	NON-COMPETING CONTINUATION	$560,211
														Subtotal = $560,211

Issue Date FY: 2022 ( Subtotal = $560,211 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	3	6/22/2022	NON-COMPETING CONTINUATION	$560,211
														Subtotal = $560,211

Issue Date FY: 2021 ( Subtotal = $571,644 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	2	6/17/2021	NON-COMPETING CONTINUATION	$571,644
														Subtotal = $571,644

Issue Date FY: 2020 ( Subtotal = $466,372 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	1	6/5/2020	NEW	$466,372
														Subtotal = $466,372

Grand Total All Awards = $2,701,502

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3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation

Award Number: R01CA244838

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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