Abstract 1034: SIGMAR1 as a novel potential prognostic biomarker that regulates PD-L1 expression in oral cancer
Authors: Chagas Pablo Shimaoka , da Silva Gabriel , de Sousa Graziella Ribeiro , Garcia Cristiana Bernadelli , Sousa Lucas Oliveira , Marcelino Rodolfo Cabral , da Silva Souza Raphael Luiz Lobo , de Matos Leandro Luongo , Kowalski Luiz Paulo , da Silva Lopes Salles Évila , Wang Lei P. , Baban Babak , Leopoldino Andreia Machado 
Published: March 2024

Abstract
Background: The SIGMAR1 receptor is a regulator of immunity and inflammation. Together, these key processes can support or restrain cancer progression and response to therapy. Nevertheless, the effect of SIGMAR1 on the modulation of oral cancer (OC) immunity is largely unknown. Here, we investigated not only the prognostic value of SIGMAR1 in OC but also, its impact on antitumor immunity response.
Methods: Were included in this study data from TCGA (Pan-Cancer analysis), multiple large datasets of OC (GSE30784; GSE42743; GSE37991, GSE31056, our cohort-based study of human OC samples and OC cell lines. Taken together, were used to performed the bioinformatics analysis and the experimental verification by several in vitro assays. The CIBERSORT analysis and Luminex assay were used to evaluate the infiltration degrees of different immune cells and also to validate the presence of chemokines and immune-stimulators, respectively, in human OC samples. To assess the role of SIGMAR1 in the modulation of the -PD-L1 expression, SIGMAR1-shRNA OC cell lines were used.
Results: We found that overexpression of SIGMAR1 was associated with poor survival rates in OC. Further, we observed that SIGMAR1 deficiency inhibited Ca2+ influx and clonogenic growth and decreased chemoresistance to cisplatin in human OC cells. Next, the SIGMAR1 expression levels were associated with infiltration degrees of M1 macrophages, Natural Killer cells and T cells (memory and helper CD4+ activated, and CD8+ cytotoxic T cells). Regarding comparison of the analytes between patients with SIGMAR1 high/low expression group, we found significant differences in the CX3CL1 (chemokine), and in immune-stimulators as CD27, CD40, and PD-L1 expression level. Importantly, this research also showed that SIGMAR1 inhibition in human OC cell lines decreases the abundance of PD-L1, both at the total protein and surface expression levels.
Conclusions: Our findings suggests SIGMAR1 not only as an emerging biomarker with promising therapeutic values to OC patients, but also gave a new insight into a potential immunotherapy strategy.
Keywords: Oral cancer; SIGMAR1; PD-L1, Immune checkpoint inhibitors.
Citation Format: Pablo Shimaoka Chagas, Gabriel da Silva, Graziella Ribeiro de Sousa, Cristiana Bernadelli Garcia, Lucas Oliveira Sousa, Rodolfo Cabral Marcelino, Raphael Luiz Lobo da Silva Souza, Leandro Luongo de Matos, Luiz Paulo Kowalski, Évila da Silva Lopes Salles, Lei P. Wang, Babak Baban, Andreia Machado Leopoldino. SIGMAR1 as a novel potential prognostic biomarker that regulates PD-L1 expression in oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1034.