Vascular checkpoints for cancer immunotherapy
Speaker: Santos Mañes
Centro Nacional de Biotecnologia (CNB) [Madrid, Spain]
Host: Xosé Bustelo
Salón de actos del Centro de Investigación del Cáncer
Cancer immunotherapy is based on the ability of immune cells, and in particular of T lymphocytes, to recognize neoantigens in tumor cells, and thus to cause their destruction. During their evolution, tumors develop multiple strategies that suppress T-cell based immune responses to evade their immunodestruction. One of these evasive mechanisms is based on the selective blockade of the entry of effector T lymphocytes into the tumor microenvironment (TME), thus generating the so-called immunologically "cold" tumors. With this, the TME becomes immunosuppressive and highly refractory to immunotherapy with immune checkpoint blockers.
The exclusion of effector T lymphocytes from tumors may occur through the activation of genetic programs induced by oncogenes (as is the case of the hyperactivation of the WNT/β-catenin pathway in neoplastic cells), or by means of tumor-cell extrinsic mechanisms, one of them involving structural and functional alterations in the tumor-associated endothelium. In the group we observed that upregulation of the extracellular superoxide dismutase (SOD3) in the TME improves endothelial function and the efficacy of chemotherapy. New data will be presented indicating a selective effect of SOD3 on the intratumoral infiltration of effector T lymphocytes, thus transforming “cold" into “hot” tumors. The levels of SOD3 are also associated with a greater infiltration of CD8 lymphocytes in a cohort of human stage II colorectal cancers, with potential consequences on the clinical outcome of these patients. It is curious that the effect of SOD3 increases tumor-infiltrating lymphocyte density through the activation of the WNT pathway in endothelial cells, thus indicating a divergent, cell type-specific effect of the WNT pathway on the infiltration of tumors by T lymphocytes.