GARP-TGF-β1
OVERVIEW
Research suggests that dysregulated transforming growth factor-β1 (TGF-β1) signaling may play a role in cancer immune escape and resistance to PD-1-mediated checkpoint inhibition. TGF-β1 signaling in the tumor microenvironment (TME) represses the antitumor function of various immune cell populations, including T cells and natural killer cells. TGF-β1 enables regulated T cells (Tregs) to suppress effector CD8+ T cell responses.1-4
- TGF-β1 is a pleiotropic cytokine that plays important roles in numerous aspects of biological processes such as cell proliferation, development, apoptosis, fibrosis, angiogenesis, wound healing, and cancer, in addition to other processes.1
- Glycoprotein-A repetitions predominant (GARP) has been identified as a critical regulator of TGF-β1 expression and activation. By binding to latent TGF-β1, GARP acts as a docking receptor that concentrates latent TGF-β on the cell surface and enhances its final activation.1
- On the cell surface, GARP-latent TGF-β1 complex associates with integrins (αVβ6 and αVβ8) to release active TGF-β1 . Mature TGF-β1 interacts with TGF-β receptors on the cell surface.
(Adapted from Metelli A, et al. Journal of Hematology & Oncology (2018) 11:24. http://creativecommons.org/licenses/by/4.0/ for CC BY 4.0 )
IMPLICATIONS IN CANCER
In a mouse model, GARP overexpression promoted Foxp3+ Treg activity, which in turn contributed to enhancing cancer progression and metastasis.2
Knocking down GARP in cancer cell lines decreases their proliferation and increases apoptosis, while overexpression enhances growth and increases resistance to both chemotherapy and radiotherapy.3
Oncogenic Expression
- GARP supports TGF-β1-driven cancer cell growth and dissemination by regulating the innate and adaptive immune system and favors tumor immune evasion.1
- GARP protein is expressed by human breast cancer, lung cancer, and colon cancer cells, where higher GARP expression correlates with worse clinical outcome.1
- Active TGF-β1 impairs adaptive anti-tumor immunity by directly inhibiting the clonal expansion and cytotoxicity of the CD8+ cytotoxic T cells (CTLs).
- Blocking TGF-β1 production by Tregs induces regression in immunotherapy resistant mouse tumors.4
- These effects are due to increased effector function of anti-tumor CD8+ cells.4
Related Research
- Metelli A, et al. Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer. Journal of Hematology & Oncology. (2018) 11:24.
- Metelli A, et al. Surface Expression of TGFb Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Res. 2016; 76(24) 7106-7117.
- de Streel G, Bertrand C, Chalon N, Liénart S, Bricard O, Lecomte S, Devreux J, Gaignage M, De Boeck G, Mariën L, Van De Walle I. Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer. Nature communications. 2020 Sep 11;11(1):1-5.
- Carrillo-Gálvez, A.B.; Quintero, J.E.; Rodríguez, R.; Menéndez, S.T.; Victoria González, M.; Blanco-Lorenzo, V.; Allonca, E.; de Araújo Farias, V.; González-Correa, J.E.; Erill-Sagalés, N.; et al. GARP Promotes the Proliferation and Therapeutic Resistance of Bone Sarcoma Cancer Cells through the Activation of TGF-β. Cell Death Dis. 2020, 11, 985.
