Tumor-Associated Extracellular Matrix Obstacles for CAR-T Cell Therapy: Approaches to Overcoming
Ilya Klabukov, Alexander E. Kabakov, Anna Yakimova, Denis Baranovskii, Д. В. Сосин, Dmitri Atiakshin, Michael Ignatyuk, Elena Yatsenko, V. A. Rybachuk, Е. С. Евстратова, Daria Eygel, D.А. Kudlаy, В. Н. Степаненко, Peter Shegay, А. Д. Каприн
Abstract
Chimeric antigen receptor (CAR)-T cell therapy yields good results in the treatment of various hematologic malignancies. However, the efficacy of CAR-T cell therapy against solid tumors has proven to be limited, primarily because the tumor-associated extracellular matrix (ECM) creates an intractable barrier for the cytotoxic CAR-T cells that are supposed to kill cancer cells. This review unravels the multifaceted role of the tumor-associated ECM in impeding CAR-T cell infiltration, survival, and functions within solid tumors. We analyze the situations when intratumoral ECM limits the efficacy of CAR-T cell therapy by being a purely physical barrier that complicates lymphocyte penetration/migration and also acts as an immunosuppressive factor that impairs the antitumor activities of CAR-T cells. In addition, we highlight promising approaches such as engineering CAR-T cells with improved capabilities to penetrate and migrate into/through the intratumoral ECM, combination therapies aimed at attenuating the high density and immunosuppressive potential of the intratumoral ECM, and others that enable overcoming ECM-related obstacles. A detailed overview of the data of relevant studies not only helps to better understand the interactions between CAR-T cells and the intratumoral ECM but also outlines potential ways to more effectively use CAR-T cell therapy against solid tumors.