Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?

• Published in: Cells (Basel, Switzerland) Switzerland), 2022-06, Vol.11 (11), p.1854
• Main Authors: Simula, Luca, Ollivier, Emma, Icard, Philippe, Donnadieu, Emmanuel
• Format: Article
• Language: English
• Subjects: adhesion; Adoptive transfer; Antigens; B-cell lymphoma; Blood vessels; Cancer; Cell adhesion molecules; Cell migration; Cell Movement; Cell therapy; Chemokines; chimeric antigen receptor; Chimeric antigen receptors; Extracellular matrix; Fibroblasts; Gene expression; Genetic engineering; Humans; Immune checkpoint; Immune Checkpoint Proteins; Leukemia; Life Sciences; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Metabolism; migration; Motility; Multiple myeloma; Neoplasms - therapy; PD-1; Proteins; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - metabolism; Remission; Review; Solid tumors; T cells; Tumor Microenvironment; Tumors
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11111854

Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually relapse after an initial remission. In most solid tumors for which CAR T-cell therapy has been tested, efficacy has been very limited. In this context, it is of paramount importance to understand the mechanisms of tumor resistance to CAR T cells. Possible factors contributing to such resistance have been identified, including inherent CAR T-cell dysfunction, the presence of an immunosuppressive tumor microenvironment, and tumor-intrinsic factors. To control tumor growth, CAR T cells have to migrate actively enabling a productive conjugate with their targets. To date, many cells and factors contained within the tumor microenvironment have been reported to negatively control the migration of T cells and their ability to reach cancer cells. Recent evidence suggests that additional determinants, such as immune checkpoint proteins, cellular metabolism, and adhesion molecules, may modulate the motility of CAR T cells in tumors. Here, we review the potential impact of these determinants on CAR T-cell motility, and we discuss possible strategies to restore intratumoral T-cell migration with a special emphasis on approaches targeting these determinants.