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Elucidating the distinct roles of T cell-polarized microglia in glioblastoma suppression and progression

Award Number: F31CA284773
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Elucidating the distinct roles of T cell-polarized microglia in glioblastoma suppression and progression - Project Summary/Abstract Glioblastoma is a grade IV diffuse astrocytoma, the deadliest and most common form of adult brain cancer. Standard of care extends survival by approximately 1-18 months, with the poorest benefits being seen by elderly patients (>70yrs). New forms of immune-based therapies, including immune checkpoint inhibitors (ICI), may turn the corner in treatments for primary and recurrent glioblastoma. Unfortunately, no clinical trial so far has shown major benefits in either survival or immune engagement for these patients. Recent findings suggest that gliomas harbor multiple and intertwined cellular sources of immune suppression that dampen ICI-initiated responses. Thus, one solution may be to not only enhance effector T cells by blocking checkpoints such as CTLA-4 and PD- 1, but to also target the immune suppressive niches in glioblastoma, the largest of which is comprised of glioma- associated microglia and macrophages (GAMs). In fact, GAMs are a highly attractive target and have been depleted in pre-clinical and clinical studies via CSF1R inhibition (PLX3397). This approach, however, yielded mixed responses in models and no response in patients. Another path may be to reprogram GAMs, but we lack insights into the pathways that promote anti-tumor GAMs. Therefore, identifying the cellular and molecular regulators of pro- and anti-tumor GAM states is the next step in unlocking new therapeutic avenues. Recent work by the Kaech lab showed that CTLA-4 blockade in orthotopic mouse models of glioblastoma reduced regulatory T cell (Treg) infiltration, increased ‘helper’ Th1 cell infiltration, and microglia exposed to Th1 cell-derived IFNg were reprogrammed into an antigen presenting (MHCII+), tumor-phagocytosing (AXL+/MER+) state; in concert, these effects significantly increased survival. This proposal will investigate how GAMs, especially the brain resident microglia, acquire and maintain distinct functional states with the hypothesis that Treg-specific signaling sustains tumor-promoting GAMs during glioblastoma progression while Th1 T cells induce tumor-killing GAMs during an effective ICI-initiated response. Two specific aims are proposed to interrogate this hypothesis. The first aim will employ single-cell spatial transcriptomics to address whether Tregs and Th1 cells are extrinsic regulators of GAM states through direct contact and/or secretory signaling, and whether these interaction axes exist in human glioblastoma. The second aim will define the intrinsic AXL/MER and related pathways regulating GAM state ‘switching’. In summary, this work will better inform GAM-targeting interventions by defining how infiltrating T cells and GAM-intrinsic signaling pathways coordinate the dynamic biology underlying pro- and anti-tumor GAM states. This application outlines the applicant’s proposed training plan, which includes diverse and multidisciplinary research mentorship, training in cutting-edge and advanced techniques, and development of broader scientific skills such as collaboration and effective communication. The research and training outlined in this proposal will prepare the applicant to conduct innovative, rigorous, and impactful research.


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 = $40,159 )
2026	2026	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	4	6/30/2026	NON-COMPETING CONTINUATION	$40,159
														Subtotal = $40,159

Issue Date FY: 2025 ( Subtotal = $42,030 )
2025	2025	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	3	7/29/2025	NON-COMPETING CONTINUATION	$42,030
														Subtotal = $42,030

Issue Date FY: 2024 ( Subtotal = $41,466 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	2	7/11/2024	NON-COMPETING CONTINUATION	$41,466
														Subtotal = $41,466

Issue Date FY: 2023 ( Subtotal = $40,186 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	001	1	7/18/2023	NEW	$0
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Research Manpower	000	1	7/18/2023	NEW	$40,186
														Subtotal = $40,186

Grand Total All Awards = $163,841

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Elucidating the distinct roles of T cell-polarized microglia in glioblastoma suppression and progression

Award Number: F31CA284773

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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