In Vitro Suppression of T Cell Proliferation Is a Conserved Function of Primary and Immortalized Human Cancer-Associated Fibroblasts

Abstract

T cell immunotherapy is now a mainstay therapy for several blood-borne cancers as well as metastatic melanoma. Unfortunately, many epithelial tumors respond poorly to immunotherapy, and the reasons for this are not well understood. Cancer-associated fibroblasts (CAFs) are the most frequent non-neoplastic cell type in most solid tumors, and they are emerging as a key player in immunotherapy resistance. A range of immortalized CAF lines will be essential tools that will allow us to understand immune responses against cancer and develop novel strategies for cancer immunotherapy. To study the effect of CAFs on T cell proliferation, we created and characterized a number of novel immortalized human CAFs lines (Im-CAFs) from human breast, colon, and pancreatic carcinomas. Im-CAFs shared similar phenotypes, matrix remodeling and contraction capabilities, and growth and migration rates compared to the primary CAFs. Using primary isolates from breast carcinoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma, we report that CAFs across major tumor types are able to potently suppress T cell proliferation in vitro. Im-CAFs retained this property. Im-CAFs are a key tool that will provide important insights into the mechanisms of CAF-mediated T cell suppression through techniques such as CRISPR-Cas9 modification, molecular screens, and pipeline drug testing.

A novel prognostic gene set for colon adenocarcinoma relative to the tumor microenvironment, chemotherapy, and immune therapy

“…In contrast, naive B cells, CD8 T cells, and CD4 memory-activated T cells were the protective factors of patients ( Yang et al, 2019 ). Moreover, CAF promotes cancer progression by inducing an immunosuppressive tumor microenvironment, rendering resistance to immunotherapy ( Miyai et al, 2020 ; Abuwarwar et al, 2021 ). Therefore, studying tumor immune infiltration helped analyze the patient’s prognosis and develop new cancer diagnosis and treatment methods.…”

3D Collagen-Nanocellulose Matrices Model the Tumour Microenvironment of Pancreatic Cancer

“…Human PDAC cell lines MIA PaCa-2 and PANC-1, and acute monocytic leukaemia THP-1 cells were purchased from the European Collection of Authenticated Cell Cultures (ECACC). Human immortalised pancreatic cancer-associated fibroblasts (CAFs) were established by the group of Dr Anne L. Fletcher ( 39 ). PDAC cells and CAFs were maintained as adherent monolayers, while THP-1 cells were grown in suspension using DMEM supplemented with 10% FBS and 1% P/S.…”

Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity

“…(B) CXCL12 secreted by CAFs binds to CXCR4 on T cells and likely contributes to T cell restriction to the tumour stroma ( 20 – 22 ). (C) CAFs limit T cell proliferation by factors including PGE2, TGF-β, VEGF and NO ( 23 – 27 ). (D) One study suggests CAF secreted TGF-β promotes differentiation of naive CD4 + T cells into FOXP3 + Tregs ( 28 ).…”

“…As T cells are sequestered in the tumour stroma, their phenotype and function are directly affected by the influence of surrounding CAFs. Multiple in vitro studies show that the presence of CAFs significantly reduces the proliferation of both CD4 + and CD8 + T cells in a contact-independent manner, suggesting this as a possible explanation for reduced TIL frequencies in CAF high tumours ( 23 – 27 ). In fact, using a pancreatic cancer cell line, Gorchs et al.…”