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Investigating molecular mechanism of immune response during cancer progression

Award Number: K00CA234842
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Investigating molecular mechanism of immune response during cancer progression - Project Summary T cell exhaustion is a dysfunctional T cell state after chronic antigen exposure, and this exhausted T cells (TEX) are often developed in chronic infection or tumor microenvironment. One of the key features of TEX is increased expression of inhibitory molecules such as Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1). These molecules work as immune checkpoints to suppress T cell function in order to prevent pathological damage from T cell hyper-activation. However, in the tumor microenvironment, these molecules limit the cytotoxic effect of T cells to kill tumor. Blocking these immune checkpoints has been shown to achieve significant clinical benefits in multiple cancer types. Despite of these successes, the majority of the patients do not achieve long-term tumor remission. Thus, it is crucial to study the underlying molecular mechanism of T cell exhaustion development, and seek for potential combination strategies with immune checkpoint blockade (ICB) to enhance and sustain T cell response in clinic. During my doctoral research, I focus on investigating the transcriptional mechanisms of T cell exhaustion development, and how transcription factors control T cell reinvigoration after PD-1 blockade. In Specific Aim 1.1, I focused on the transcriptional mechanisms of effector T cell loss and TEX progenitor establishment during chronic antigen exposure. Using single cell RNA sequencing (sc-RNA-Seq), we found two distinct transcriptional networks in the chronic effector T cells and the TEX progenitors, and we systematically described the molecular mechanism of TEX development. In Specific Aim 1.2, I focus on establishing a T cell based in vivo CRISPR-Cas9 screening system (RetroCRISPR) to functionally study transcriptional mechanisms during T cell reinvigoration by PD-1 blockade. These studies will not only discover novel mechanisms of T cell exhaustion, but also provide high dimensional profiling or high throughput screening systems for the field to study T cell response. In Specific Aim 2, I plan to extend my RetroCRISPR system into dissecting the complexity of tumor microenvironment, and I will search for potential combination strategies with ICB to enhance T cell response. The overall goal for my current projects and future plans is to discover cell intrinsic and extrinsic mechanisms affecting T cell response, and design optimal immune therapeutic strategies for long-term tumor remission.


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	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Cause and Prevention Research	000	7	3/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $97,605 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Cause and Prevention Research	000	7	11/14/2023	NON-COMPETING CONTINUATION	$97,605
														Subtotal = $97,605

Issue Date FY: 2023 ( Subtotal = $93,150 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	6	11/21/2022	NON-COMPETING CONTINUATION	$93,150
2023	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	10/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $93,150

Issue Date FY: 2022 ( Subtotal = $88,695 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	005	5	5/25/2022	NON-COMPETING CONTINUATION	-$240
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	004	5	4/8/2022	NON-COMPETING CONTINUATION	$88,935
2022	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	003	4	2/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,921
2022	2021	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	002	3	2/17/2022	EXTENSION WITH OR WITHOUT FUNDS	-$1,921
2022	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	4	12/24/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$36,633
2022	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	12/24/2021	EXTENSION WITH OR WITHOUT FUNDS	-$36,633
														Subtotal = $88,695

Issue Date FY: 2021 ( Subtotal = $90,396 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	1/22/2021	EXTENSION WITH OR WITHOUT FUNDS	$90,396
														Subtotal = $90,396

Grand Total All Awards = $369,846

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Investigating molecular mechanism of immune response during cancer progression

Award Number: K00CA234842

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/08/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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