Targeting Cancer-Associated Fibroblasts

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Definition of CAF

Cancer-associated fibroblasts (CAFs) are a unique cell population of the tumor microenvironment (TME) and play an important contributory role in the TME. CAFs are recognized as a heterogeneous cell type in TME and originate from various cells. They can originate from normal tissue-resident fibroblasts, as well as a number of non-fibroblastic mesenchymal cells or even tumor cells (Fig.1). As a source of growth factors, cytokines, chemokines, and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming, and therapeutic resistance.

Fig.1 Origin of CAFs. (Louault, 2020)

Activation of CAFs

Fibroblasts are one of the abundant factors in TME which have a major impact on tumor behavior. Although normal fibroblasts demonstrate anti-tumor effects, CAFs are principal participants in tumor growth and invasion. Cancer cells can drive fibroblast activation. In addition to malignant cells, endothelial, inflammatory, and immune cells in the TME also secrete mediators of fibroblast activation. Moreover, activated fibroblasts produce factors and matrix that drive their autocrine activation in a feed-forward manner, as fibroblasts are responsive to substratum composition and stiffness.

Functions of CAFs in TME

CAFs are a substantial source of matrix production, growth factors, cytokines, and exosomes. CAFs produce large amounts of ECM proteins creating a favorable stromal environment. Soluble factors can contribute to changes in tumor growth, invasion, and the immune microenvironment, which is also affected by the altered metabolic state of the tumor. The secretome of CAFs also influences other components of the TME, including macrophages, T cells, and tumor cells. Moreover, the exchange of metabolites between cancer cells and CAFs is an additional avenue to support tumor growth.

Summary of CAFs Functions

Promotion of tumor growth and maintenance of stemness
Migration, pro-invasive and metastatic activity
Angiogenesis activity
Remodeling extracellular matrix (ECM)
Immunosuppressive activity
Anti-tumorigenic activity
Promotion of chemoresistance

Origin of CAFs. Fig.2 Summary of CAF functions and the mechanisms by which they are achieved. (Sahai, 2020)

CAF-targeted Therapeutic Approaches

Dugs that target CAFs have emerged as a critical complement to immunotherapies in multiple solid tumors. There are many strategies under investigation for targeting CAFs including depletion, blocking their tumor-promoting functions, inhibiting their activation, and skewing them to a normal or even tumor-suppressive phenotype.

Depletion of CAFs

Fibroblast activation protein (FAP) has emerged over the last decade as the most promising immunotherapeutic target. Targeting FAP attenuates activated tumor-promoting traits in CAFs and augments immunotherapy treatments. There are many strategies to deplete CAFs including CAR-T therapy, monoclonal antibody, oncolytic viruses, etc.

Normalization of CAFs

NADPH oxidase 4 (NOX4) is one of the target genes of TGF-β signaling in fibroblasts. NOX4 inhibition can prevent and reverse CAFs activation, and reduce ECM deposition and CAF-mediated tumor cell invasion and migration. TGF-β blockade and angiotensin receptor inhibition (e.g. Vitamin D) are alternative approaches to inhibit CAFs activation.

Targeting downstream effectors of CAFs

Targeting downstream effectors of CAFs, mainly CAF-derived cytokines and chemokines, can interfere with communication between cancer cells and stromal cells including CAFs. While inhabiting a single pathway may exert some efficacy, it is unlikely to eradicate tumors.

Targeting CAF-derived ECM proteins

ECM modifications play an important role in tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc). Therefore, targeting ECM components holds much promise for improved cancer management. ECM and associated signaling can be targeted to induce stromal depletion and increase immune T cell infiltration.

Fig.3 Principal strategies for CAF-directed anti-cancer therapies. (Mhaidly, 2021)

Creative Biolabs is committed to providing flexible services and products to support every aspect of our clients' needs. Now we are dedicated to developing strategies to reshape TME. CAFs are important components in TME and attract increasing attention as a therapeutic target in cancer. Various CAF marker antibodies at our lab are available for CAF validation. Custom services include CAR-T, Oncolytic Virus, antibody development services, etc. In addition, we offer expertise to help accelerate the process of targeting CAFs.

References

Louault, K.; et al. Cancer-associated fibroblasts: Understanding their heterogeneity. Cancers, 2020, 12(11): 3108.
Sahai, E.; et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nature Reviews Cancer, 2020, 20(3): 174-186.
Mhaidly, R.; Mechta-Grigoriou, F. Role of cancer-associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer. Immunological Reviews. 2021.