Potential of fluoropyrimidine to be an immunologically optimal partner of immune checkpoint inhibitors through inducing immunogenic cell death for thoracic malignancies

BackgroundImmune checkpoint inhibitors (ICIs) are a revolutionary paradigm in the treatment of thoracic malignancies and chemoimmunotherapy is a current standard care in this field. Chemotherapeutic agents are known to induce not only direct cytotoxic effects on tumor cells but also immune modulating effects, such as stimulating immunogenic cell death (ICD). Currently, either pemetrexed (PEM) or taxane plus platinum are combined with ICIs for patients with non-small cell lung cancer (NSCLC); however, it is still unknown whether these agents are immunologically optimal partners for ICIs.MethodsTo determine the immunologically optimal chemotherapeutic agent, we first evaluated the ability of several chemotherapeutic agents, including platinum, PEM, taxane, and 5-fluorouracil (5-FU) to induce ICD using several thoracic tumor cell lines in vitro. ICD was evaluated by the cell surface expression of calreticulin (CRT) and adenosine-triphosphate (ATP) secretion. We further performed an antitumor vaccination assay in vivo.Results5-FU induced cell surface expression of CRT and ATP secretion most efficiently among the several chemotherapeutic agents. This effect was enhanced when it was combined with platinum. In the antitumor vaccination assay in vivo, we found that vaccination with dying-AB1-HA (a murine malignant mesothelioma cell line) cells treated with 5-FU, but neither PEM nor PTX, reduced the tumor growth of living-AB1-HA cells inoculated 1 week after vaccination by recruiting CD3+CD8+ T cells into the tumor microenvironment.ConclusionOur findings indicate that fluoropyrimidine can be an immunologically optimal partner of ICIs through the induction of ICD for thoracic malignancies. Fluoropyrimidine most efficiently enhanced the antitumor immune responses by CD8+ T cells through the induction of cell surface expression of CRT and ATP secretion in thoracic tumor cells. These findings indicate that fluoropyrimidine may be an immunologically optimal partner of ICIs for thoracic malignancies.image