PXD015804-1

PXD015804 is an original dataset announced via ProteomeXchange.

Title	Targeting immunosuppressive macrophages overcomes PARP-inhibitor resistance in BRCA1-associated triple-negative breast cancer
Description	Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.
HostingRepository	PRIDE
AnnounceDate	2021-03-25
AnnouncementXML	Submission_2021-03-24_23:42:39.215.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jennifer Guerriero
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-10-14 02:04:33	ID requested
⏵ 1	2021-03-24 23:42:40	announced

Mehta AK, Cheney EM, Hartl CA, Pantelidou C, Oliwa M, Castrillon JA, Lin JR, Hurst KE, de Oliveira Taveira M, Johnson NT, Oldham WM, Kalocsay M, Berberich MJ, Boswell SA, Kothari A, Johnson S, Dillon DA, Lipschitz M, Rodig S, Santagata S, Garber JE, Tung N, Y, é, lamos J, Thaxton JE, Mittendorf EA, Sorger PK, Shapiro GI, Guerriero JL, Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer, 2(1):66-82(2021) [pubmed]

submitter keyword: TAM (tumor associated macrophage), PARP, TMT, Lumos

Jennifer L. Guerriero, PhD
contact affiliation	Director of The Breast Tumor Immunology Laboratory Women’s Cancer Program Dana-Farber Cancer Institute Instructor in Medicine Harvard Medical School
contact email	jennifer_guerriero@dfci.harvard.edu
lab head
Jennifer Guerriero
contact affiliation	Dana-Farber Cancer Institute
contact email	Jennifer_Guerriero@dfci.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015804
     1. Label: PRIDE project
     2. Name: Targeting immunosuppressive macrophages overcomes PARP-inhibitor resistance in BRCA1-associated triple-negative breast cancer