S100A9 enhances tumor immune suppression and cancer cell survival in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer associated with a poor prognosis. However, there have been few advancements in improving the survival of SCLC patients in recent decades. This study shows that the S100A9 protein is highly expressed in SCLC patients and several highly aggressive SCLC cell lines. Furthermore, we showed that S100A9 expression inversely correlates with overall survival in SCLC patients. S100A9 increases the survival and migration of SCLC cells by activating Akt and GSK3α/β/Snail pathways. In addition, S100A9 reduces tumor cell autophagy through MAGE-A3. S100A9 depletion or pharmacological inhibition using tasquinimod reduced tumor growth and metastasis in vivo. Importantly, we observed that S100A9 downregulation or tasquinimod treatment alone or combined with cisplatin reduces the recruitment of MDSCs. Furthermore, tasquinimod treatment alone or combined with cisplatin significantly enhanced tumor infiltration of activated CD8+ (CD69-positive) T cells. Overall, our results, for the first time, show that S100A9 enhances SCLC progression and metastasis by altering the tumor microenvironment, and its inhibition using tasquinimod alone or in combination with chemotherapy could be developed as a promising therapeutic strategy for SCLC.