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.
Highlights
Immune surveillance is a monitoring process in which immune cells target transformed or malignant cells for recognition and elimination [1]
We obtained primary human Cancer-associated fibroblasts (CAFs) from breast carcinoma, colorectal carcinoma, and pancreatic adenocarcinoma
The gene encoding simian virus 40 large T (SV40LT) was first cloned into pDONR221 and subcloned into a piggyBac expression plasmid upstream of an internal ribosome entry site (IRES)-green fluorescent protein (GFP) or -mCherry site (Figure 1A)
Summary
Immune surveillance is a monitoring process in which immune cells target transformed or malignant cells for recognition and elimination [1]. T cell cancer immunotherapies have shown promising results across multiple types of malignancies, by improving the host immune response against tumors and overcoming immune evasion. Examples of these therapies are immune checkpoint blockade and chimeric antigen receptor (CAR) T cells, which respectively seek to reawaken or infuse anti-tumor T cells [2,3]. Despite the clinical success of immune checkpoint inhibitors and CAR-T cells in treating several circulating hematologic cancers, they have not been as effective in solid tumors [4]. Emerging evidence suggests that this could be a major obstacle for immunotherapies [5]
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