Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer

Authors

Kathleen M McAndrews
Yang Chen
J Kebbeh Darpolor
Xiaofeng Zheng
Sujuan Yang
Julienne L Carstens
Bingrui Li
Huamin Wang
Toru Miyake
Pedro Correa de Sampaio
Michelle L Kirtley
Mariangela Natale
Chia-Chin Wu
Hikaru Sugimoto
Valerie S LeBleu
Raghu Kalluri

Publication Date

6-2-2022

Journal

Cancer Discovery

Abstract

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Employing single-cell RNA-sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAFs) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs that leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAFs) and tumor-restraining αSMA+ CAFs (TR-CAFs) differentially regulate cancer-associated pathways and accumulation of Tregs. Improved efficacy of gemcitabine is observed when IL-6 is deleted from αSMA+ CAFs but not from FAP+ CAFs employing dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL-6 synergizes with anti-PD1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response.

Keywords

Animals, Cancer-Associated Fibroblasts, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Fibroblasts, Humans, Interleukin-6, Mice, Pancreatic Neoplasms, Tumor Microenvironment

DOI

10.1158/2159-8290.CD-20-1484

PMID

35348629

PMCID

PMC9399904

PubMedCentral® Posted Date

12-2-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes