Fibroblasts and macrophages cooperate to create a pro-tumorigenic and immune resistant environment via activation of TGF-β/IL-6 pathway in neuroblastoma

Kevin Louault; Tania Porras; Meng-Hua Lee; Sakunthala Muthugounder; Rebekah J. Kennedy; Laurence Blavier; Emily Sarte; G. Esteban Fernandez; Fusheng Yang; Bruce R. Pawel; Hiroyuki Shimada; Shahab Asgharzadeh; Yves A. DeClerck

doi:10.1080/2162402X.2022.2146860

OncoImmunology (Dec 2022)

Fibroblasts and macrophages cooperate to create a pro-tumorigenic and immune resistant environment via activation of TGF-β/IL-6 pathway in neuroblastoma

Kevin Louault,
Tania Porras,
Meng-Hua Lee,
Sakunthala Muthugounder,
Rebekah J. Kennedy,
Laurence Blavier,
Emily Sarte,
G. Esteban Fernandez,
Fusheng Yang,
Bruce R. Pawel,
Hiroyuki Shimada,
Shahab Asgharzadeh,
Yves A. DeClerck

Affiliations

Kevin Louault: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
Tania Porras: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
Meng-Hua Lee: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
Sakunthala Muthugounder: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
Rebekah J. Kennedy: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
Laurence Blavier: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
Emily Sarte: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
G. Esteban Fernandez: The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA
Fusheng Yang: Department of Pathology, University of Southern California, Los Angeles, CA, USA
Bruce R. Pawel: Department of Pathology, University of Southern California, Los Angeles, CA, USA
Hiroyuki Shimada: Departments of Pathology and Pediatrics, Stanford University, Stanford, CA, USA
Shahab Asgharzadeh: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA
Yves A. DeClerck: Cancer and Blood Diseases Institute, Department of Pediatrics, Children’s Hospital Los Angeles and the University of Southern California, Los Angeles, CA, USA

DOI: https://doi.org/10.1080/2162402X.2022.2146860
Journal volume & issue: Vol. 11, no. 1

Abstract

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Tumor-associated macrophages (TAM) and cancer-associated fibroblasts (CAF) and their precursor mesenchymal stromal cells (MSC) are often detected together in tumors, but how they cooperate is not well understood. Here, we show that TAM and CAF are the most abundant nonmalignant cells and are present together in untreated human neuroblastoma (NB) tumors that are also poorly infiltrated with T and natural killer (NK) cells. We then show that MSC and CAF-MSC harvested from NB tumors protected human monocytes (MN) from spontaneous apoptosis in an interleukin (IL)-6 dependent mechanism. The interactions of MN and MSC with NB cells resulted in a significant induction or increase in the expression of several pro-tumorigenic cytokines/chemokines (TGF-β1, MCP-1, IL-6, IL-8, and IL-4) but not of anti-tumorigenic cytokines (TNF-α, IL-12) by MN or MSC, while also inducing cytokine expression in quiescent NB cells. We then identified a TGF-β1/IL-6 pathway where TGF-β1 stimulated the expression of IL-6 in NB cells and MSC, promoting TAM survival. Evidence for the contribution of TAM and MSC to the activation of this pathway was then provided in xenotransplanted NB tumors and patients with primary tumors by demonstrating a direct correlation between the presence of CAF and p-SMAD2 and p-STAT3. The data highlight a new mechanism of interaction between TAM and CAF supporting their pro-tumorigenic function in cancer.

Published in OncoImmunology

ISSN: 2162-402X (Online)
Publisher: Taylor & Francis Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy; Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.tandfonline.com/journals/koni

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