Fibroblasts Influence the Efficacy, Resistance, and Future Use of Vaccines and Immunotherapy in Cancer Treatment

Abstract

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

Non-conventional and Investigational PET Radiotracers for Breast Cancer: A Systematic Review

“…In the last decade, researchers have attempted to better study CAF cells and their role in cancer evolution, which is correlated with T-cell immunosuppression and lead to poor clinical outcome ( 192 ), also by developing specific probes, such as new radiotracers targeting CAF-dependent pathways.…”

NSCLC Biomarkers to Predict Response to Immunotherapy with Checkpoint Inhibitors (ICI): From the Cells to In Vivo Images

“…Indeed, a greater understanding of how tumor stroma and TME comprehensively affect immunotherapy will provide important advances: CAF markers correlate with T cell immunosuppression, blocking the effects of both CD8 + T cells and NK cells, especially through the release of various chemokines and cytokines (mainly IL-6 production), leading to poor clinical outcome. It is for these reasons that CAF depletion and targeting CAF-dependent pathways may indirectly lead to malignant cell death through both immune-dependent and immune-independent mechanisms [ 196 ].…”

Cancer Vaccines and Immunotherapy for Tumor Prevention and Treatment

“…Development of prophylactic and therapeutic vaccines for cancer is far more challenging than developing vaccines against viral or bacterial diseases because of the limited antigenicity of cancer cells; immune evasion pathways that block T-cell activation, suppress the TME, and others; differences in ideal effector mechanisms to resist microbial pathogenesis (often antibodies) and eliminate cancer (often cytotoxic CD8 + T-cells); and many more. Indeed, Sliker and Campbell discuss challenges created by the continuously evolving TME and downstream impacts on the tumor immune landscape [7]. They highlight research showing that fibroblasts in tumors can impact the TME and profoundly affect the generation of immune responses against tumor cells by cell-cell contacts and secretion of various cytokines.…”