Ovarian cancer-derived IL-4 promotes immunotherapy resistance.

CCL7 IL-4 Perturb-map immunotherapy intratumoral heterogeneity macrophages multiplex imaging ovarian cancer spatial CRISPR screens spatial genomics tumor immunology tumor microenvironment tumor neighborhood type 2 immunity

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
25 Oct 2024
Historique:
received: 17 09 2023
revised: 20 04 2024
accepted: 03 10 2024
medline: 1 11 2024
pubmed: 1 11 2024
entrez: 31 10 2024
Statut: aheadofprint

Résumé

Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.

Identifiants

DOI: 10.1016/j.cell.2024.10.006 PMID: 39481380
pubmed: 39481380
pii: S0092-8674(24)01154-1
doi: 10.1016/j.cell.2024.10.006
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests B.D.B. has a patent application on the Pro-Codes, which have been licensed to Immunai and Noetik. P.K.S. is co-founder of Glencoe Software and member of the SAB for RareCyte, NanoString, and Montai Health; he holds equity in Glencoe and RareCyte. N.R. is the founder of R&A Data.

Auteurs

Gurkan Mollaoglu (G)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Alexander Tepper (A)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Chiara Falcomatà (C)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Hunter T Potak (HT)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Luisanna Pia (L)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Angelo Amabile (A)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Jaime Mateus-Tique (J)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Noam Rabinovich (N)

R&A Data, New York, NY, USA.

Matthew D Park (MD)

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Nelson M LaMarche (NM)

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Rachel Brody (R)

Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Lindsay Browning (L)

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Jia-Ren Lin (JR)

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.

Dmitriy Zamarin (D)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Peter K Sorger (PK)

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.

Sandro Santagata (S)

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.

Miriam Merad (M)

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Alessia Baccarini (A)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: alessia.baccarini@mssm.edu.

Brian D Brown (BD)

Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: brian.brown@mssm.edu.

Classifications MeSH