Exploring the role of PlexinA4 in cytotoxic T cells: insights for antitumor immune response & cancer immunotherapy

The immune system is a defense mechanism that can be activated upon encountering cancer cells. After its activation, recruited immune components, like cytotoxic T cells (CTLs) can recognize and directly kill the cancer cells. However, cancer cells can evade the immune system by creating an immunosuppressive tumor microenvironment (TME). Pharmacologic reactivation of CTLs, immunotherapy, is an interesting strategy to treat cancer. Nevertheless, many cancer types remain refractory to this therapy. Plexins are receptors for the attractive/repulsive guidance molecules semaphorins in the nervous system, which are also known to be expressed on immune cells. Starting from previous observations of the host lab that a semaphorin-plexin signaling cascade underpin an important pathway in the immunosuppressive TME, we started to investigate how PlexinA4 can influence tumor progression. Using chimeric mice with a genetic deletion of PlexinA4 in immune cells, we observed a strong reduction in tumor volume in a triple-negative breast cancer model, accompanied by an increase in CTL infiltration in both the lymph nodes (LNs) and primary tumor. Additionally, in a tumor-free environment, we observed that CTLs lacking PlexinA4 expression, have increased homing to the LNs. Based on these observations, this project will further unravel the role of PlexinA4 in CTLs during tumor progression and potentially identify a novel therapeutic approach to enable optimal immunotherapy in refractory tumors.