Unveiling immune cell response disparities in human primary cancer-associated fibroblasts between two- and three-dimensional cultures.

Autor: Yang JP; Takeda Development Center Americas, Inc., San Diego, California, United States of America., Kulkarni NN; Takeda Development Center Americas, Inc., San Diego, California, United States of America., Yamaji M; Takeda Development Center Americas, Inc., San Diego, California, United States of America., Shiraishi T; Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa, Japan., Pham T; BioTuring, San Diego, California, United States of America., Do H; BioTuring, San Diego, California, United States of America., Aiello N; Bristol-Myers Squibb, Princeton, New Jersey, United States of America., Shaw M; Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States of America., Nakamura T; Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa, Japan., Abiru A; Takeda Pharmaceutical Company Ltd, Fujisawa, Kanagawa, Japan., Gavva NR; Takeda Development Center Americas, Inc., San Diego, California, United States of America., Horman SR; Takeda Development Center Americas, Inc., San Diego, California, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Dec 19; Vol. 19 (12), pp. e0314227. Date of Electronic Publication: 2024 Dec 19 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0314227
Abstrakt: Cancer-associated fibroblasts (CAFs) play pivotal roles in solid tumor initiation, growth, and immune evasion. However, the optimal biomimetic modeling conditions remain elusive. In this study, we investigated the effects of 2D and 3D culturing conditions on human primary CAFs integrated into a modular tumor microenvironment (TME). Using single-nucleus RNA sequencing (snRNAseq) and Proteomics' Proximity Extension Assays, we characterized CAF transcriptomic profiles and cytokine levels. Remarkably, when cultured in 2D, CAFs exhibited a myofibroblast (myCAF) subtype, whereas in 3D tumor spheroid cultures, CAFs displayed a more inflammatory (iCAF) pathological state. By integrating single-cell gene expression data with functional interrogations of critical TME-related processes [natural killer (NK)-mediated tumor killing, monocyte migration, and macrophage differentiation], we were able to reconcile form with function. In 3D TME spheroid models, CAFs enhance cancer cell growth and immunologically shield cells from NK cell-mediated cytotoxicity, in striking contrast with their 2D TME counterparts. Notably, 3D CAF-secreted proteins manifest a more immunosuppressive profile by enhancing monocyte transendothelial migration and differentiation into M2-like tumor-associated macrophages (TAMs). Our findings reveal a more immunosuppressive and clinically relevant desmoplastic TME model that can be employed in industrial drug discovery campaigns to expand the cellular target range of chemotherapeutics.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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