Monday, June 30, 2025 6/30/2025

Cell lineage as an indicator of immune response in neuroblastoma

Award Number: R01CA271605
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/16/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

Group Awards By:

View Award Description

Cell lineage as an indicator of immune response in neuroblastoma - PROJECT SUMMARY/ABSTRACT The sparse landscape of targetable mutations in pediatric cancers in general and neuroblastoma (NB) in particular, together with the recent successes of the anti-GD2 antibody, dinutuximab (2), provides a compelling rationale for further development of immune-based treatment strategies against this devastating cancer. However, responses to adoptive immunotherapy and checkpoint blockade have met with limited success, partly due to an incomplete understanding of the mechanisms underlying immune responsiveness or resistance in this tumor marked by significant heterogeneity. We undertook an unbiased clustering analysis of transcriptional signatures derived from a large primary NB data set and identified a subset of tumors, characterized by the high expression of immune response activation and suppression genes, and indicating the potential for eliciting an anti-tumor immune response. These signatures were seen mainly in tumors of the mesenchymal (MES) lineage, one of the two epigenetically regulated cell states in NB, comprised of undifferentiated malignant cells with primitive neural crest-like properties. By contrast, tumors with committed, adrenergic (ADR) neuron-like malignant cells were less immunogenic and exhibited PRC2-mediated suppression of key tumor cell-intrinsic immune activation genes. These promising results led to our central hypothesis that cell lineage state is an important predictor of immune therapy response in NB. In Aim 1, we will elucidate the epigenetic mechanisms underlying lineage-specific activation of immune response genes. Aim 2 will assess lineage- dependent functions of cytotoxic T cells in tumor control by determining whether MES NB cells possess an inflamed TME that facilitates cell-based therapies. In Aim 3, we will determine whether the increased expression of NK cell receptor ligands in MES tumors translates into response to NK cell therapy and whether PRC2 inhibition will augment such responses in ADR tumors alone or in combination dinutuximab. Together, these studies are expected to provide a compelling rationale for the use of tumor cell lineage for the selection of patients who are most likely to benefit from immunotherapy and to pre-clinically validate treatment strategies involving combinations of epigenetic and immune-based therapies to target the specific immune evasion mechanisms deployed by NB cells, our long-term goal.


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 = $405,378 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	4	4/21/2025	NON-COMPETING CONTINUATION	$364,840
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	4	6/2/2025	NON-COMPETING CONTINUATION	$40,538
														Subtotal = $405,378

Issue Date FY: 2024 ( Subtotal = $385,110 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	3	4/25/2024	NON-COMPETING CONTINUATION	$385,110
														Subtotal = $385,110

Issue Date FY: 2023 ( Subtotal = $397,270 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	5/15/2023	NON-COMPETING CONTINUATION	$397,270
														Subtotal = $397,270

Issue Date FY: 2022 ( Subtotal = $405,378 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	6/16/2022	NEW	$405,378
														Subtotal = $405,378

Grand Total All Awards = $1,593,136

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Cell lineage as an indicator of immune response in neuroblastoma

Award Number: R01CA271605

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/16/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer