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MAPK as target of glioma immunoediting by CD8 T-cells, and predictor of response to immunotherapy

Award Number: R01NS110703
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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MAPK as target of glioma immunoediting by CD8 T-cells, and predictor of response to immunotherapy - SUMMARY Whereas randomized trials for PD1 blockade in glioblastoma (GBM) are negative,2 a subset of these patients do respond to immunotherapy.3 Determining the basis of response will result in immunotherapy being effectively used for some patients. We recently reported the analysis of 66 recurrent GBM patients that were treated with PD1 blockade.1 Whereas response was defined based on imaging criteria, responsive patients exhibited significant increased survival that was independent of clinical characteristics or additional treatments. 30% of tumors of responsive patients had enrichment of BRAF and PTPN11 activating mutations, which stimulate MAPK pathway signaling.1 Therefore, molecular indicators of response to PD1 blockade for the majority of patients remain unidentified. We performed immunohistochemistry for phosphorylation of p38 and ERK, two effectors of this pathway. Extent of positivity for these markers was predictive of overall survival following PD1 blockade. Of relevance to our patient tumor studies, we modeled the effect of CD8 T-cell depletion on tumor progression on mouse transgenic gliomas that develop de novo. In this setting, CD8 T-cell depletion resulted in immunogenic tumors that upon transplantation, preferentially engrafted in recipients with CD8 T-cell depletion as opposed to immunocompetent hosts. Gliomas generated in the absence of CD8 T-cells showed upregulation of Braf and Ptpn11, and associated MAPK activation indicated by phosphorylation of p38 and Erk. CD8 T-cell depletion during glioma development also led to robust increase in tumor associated macrophages/microglia (TAM), and gene expression of pro-inflammatory TAM. MAPK activity correlated with TAM markers in mouse transgenic gliomas and human GBM, and with several chemokines that promote pro-inflammatory TAM. A CRISPR knock- out screen for the kinome on intracranial gliomas also implicated MAPK in T-cell recognition of tumor cells. These findings suggest that MAPK activity in tumor cells (that is suppressed by CD8 T-cells during glioma progression), promotes pro-inflammatory TAM. We hypothesize that GBM with elevated MAPK signaling, are more susceptible to CD8 T-cell recognition, as this pathway promotes anti-tumoral TAM. Thus, the subset of GBM that have MAPK signaling are susceptible to PD1 blockade and CAR T-cell immunotherapy. To investigate this, we will SA1) Determine the effects of CD8 T-cell depletion during glioma development on TAM phenotype. SA 2) Determine whether MAPK signaling promotes anti-tumoral glioma TAM. SA 3) Determine the effect of modulating glioma MAPK signaling on response to PD1 blockade and CAR T-cell therapy. We will use transgenic models in which tumors develop de novo, cell lines with varying levels of MAPK activation, genetic MAPK manipulation as well as clinically available drugs inhibit and/or promote MAPK signaling that cross the blood-brain barrier. Successful execution of these studies will establish a novel immune-related role of MAPK signaling in glioma. We will determine whether MAPK signaling by tumor cells influences response to PD1 blockade, and CAR T-cell therapy.


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 = $0 )
2025	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $364,720 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/25/2023	NON-COMPETING CONTINUATION	$338,400
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/25/2024	NON-COMPETING CONTINUATION	$26,320
														Subtotal = $364,720

Issue Date FY: 2023 ( Subtotal = $376,000 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/23/2022	NON-COMPETING CONTINUATION	$338,400
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/31/2023	NON-COMPETING CONTINUATION	$37,600
														Subtotal = $376,000

Issue Date FY: 2022 ( Subtotal = $376,000 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/31/2022	NON-COMPETING CONTINUATION	$37,600
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/20/2021	NON-COMPETING CONTINUATION	$338,400
														Subtotal = $376,000

Issue Date FY: 2021 ( Subtotal = $372,867 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/13/2021	NON-COMPETING CONTINUATION	$372,867
														Subtotal = $372,867

Issue Date FY: 2020 ( Subtotal = $371,300 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/29/2020	NEW	$0
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/3/2020	NEW	$371,300
														Subtotal = $371,300

Grand Total All Awards = $1,860,887

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MAPK as target of glioma immunoediting by CD8 T-cells, and predictor of response to immunotherapy

Award Number: R01NS110703

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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