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Mechanisms underlying tumor-infiltrating tissue resident memory T cell generation and maintenance

Award Number: K08CA230164
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/03/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Mechanisms underlying tumor-infiltrating tissue resident memory T cell generation and maintenance - Project Summary/Abstract Immunotherapy is rapidly becoming a mainstream treatment of cancers, nonetheless, less than 30% of patients benefit from this approach. Thus, there is an urgent need to develop novel immunotherapeutic agents for patients who do not respond to currently available immunotherapies. Our goal is to identify such novel targets by investigating the molecular mechanisms that drive the generation and maintenance of a distinct class of tumor-infiltrating cytotoxic T lymphocytes (CTLs)—tissue-resident memory cells (TRM). We recently performed the largest unbiased survey of over 100 transcriptomes from purified CD8+ CTLs isolated from tumors of treatment-naïve patients with early-stage lung cancer and provocatively showed that TRM were key players in mediating robust anti-tumor immune responses (Nature Immunology 2017). We revealed that TRM was selectively enriched in tumors with a high density of tumor-infiltrating lymphocytes (TILs) and displayed enhanced cytotoxicity and proliferation, implying better anti-tumor activity. We also showed that a higher density of TRM cells in tumors predicted better survival outcomes. Given that only a subset of tumors is enriched for TRM, which mounts an effective anti-tumor response, it is crucial to understand the key signals that drive TRM cell generation and maintenance within tumors. We hypothesize that TRM development likely involves several molecular switches (like transcription factors) that regulate migration, tissue retention, survival and response to local milieu (tumor). Here, we propose to directly analyze the transcriptome and epigenome of tumor-infiltrating TRM CTLs to define the molecular pathways governing TRM development by utilizing genomic tools such as single-cell sequencing, ATAC-sequencing and histone ChIP-Seq. We will also functionally validate the role of one such important candidate pathway, i.e., CD39 signaling, in promoting TRM, given that our recent studies show differential high expression of CD39 on TRM-rich TILs. CD39 has been associated with immunesuppression as well as T memory formation, hence the consequences of CD39 expression are unclear. Given that tumor-infiltrating TRM mount clinically beneficial anti-tumor immune responses, we hypothesize that higher expression of CD39 on TRM cells may preferentially protect them from ATP-induced cell death and enable persistence within tumors. We will evaluate the functional role of CD39 in vivo in the generation and maintenance of tumor-infiltrating TRM by testing effects of CD39 abrogation utilizing transplantable and autochthonous mouse tumor models and CD8+ T cell-specific CD39-knockout mice. Furthermore, CD39 knock-down or overexpression studies will be performed in patient-derived tumor- infiltrating TRM cells in vitro and the effects on TRM activation, apoptosis, proliferation, cytotoxicity and cytokine production will be evaluated. In summary, our studies will provide important insights into the molecular signals that promote robust anti-tumor TRM immune response, which may enable immunotherapeutic targeting of critical pathways and design of vaccines that will aid TRM generation.


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	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	5	6/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $275,122 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	5	3/21/2023	NON-COMPETING CONTINUATION	$275,122
														Subtotal = $275,122

Issue Date FY: 2022 ( Subtotal = $275,070 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	4	3/31/2022	NON-COMPETING CONTINUATION	$275,070
														Subtotal = $275,070

Issue Date FY: 2021 ( Subtotal = $275,019 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	3	3/2/2021	NON-COMPETING CONTINUATION	$275,019
														Subtotal = $275,019

Issue Date FY: 2020 ( Subtotal = $274,969 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	2	3/17/2020	NON-COMPETING CONTINUATION	$274,969
														Subtotal = $274,969

Issue Date FY: 2019 ( Subtotal = $274,920 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	1	4/3/2019	NEW	$274,920
														Subtotal = $274,920

Grand Total All Awards = $1,375,100

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Mechanisms underlying tumor-infiltrating tissue resident memory T cell generation and maintenance

Award Number: K08CA230164

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/03/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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