Background: Pancreatic cancer presents extremely poor prognosis due to the difficulty of early diagnosis, low resection rate, and high rates of recurrence and metastasis. Immune checkpoint blockades have been widely used in many cancer types but showed limited efficacy in pancreatic cancer. The current study aimed to evaluate the landscape of tumor microenvironment (TME) of pancreatic cancer and identify the potential markers of prognosis and immunotherapy efficacy which might contribute to improve the targeted therapy strategy and efficacy in pancreatic cancer in the context of predictive, preventive, and personalized medicine (PPPM).
Methods: In the current study, a total of 382 pancreatic samples from the datasets of Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were selected. LM22 gene signature matrix was applied to quantify the fraction of immune cells based on "CIBERSORT" algorithm. Weighted Gene Co-expression Network Analysis (WGCNA) and Molecular Complex Detection (MCODE) algorithm was applied to confirm the hub-network of immune-resistance phenotype. A nomogram model based on COX and Logistic regression was constructed to evaluate the prognostic value and the predictive value of hub-gene in immune-response. The role of transmembrane protein 92 (TMEM92) in regulating cell proliferation was evaluated by MTS assay. Western blot and Real-time PCR were applied to assess the biological effects of PD-L1 inhibition by TMEM92. Moreover, the effect of TMEM92 in immunotherapy was evaluated with PBMC co-culture and by MTS assay.
Results: Two tumor-infiltrating immune cell (TIIC) phenotypes were identified and a weighted gene co-expression network was constructed to confirm the 167 gene signatures correlated with immune-resistance TIIC subtype. TMEM92 was further identified as a core gene of 167 gene signature network based on MCODE algorithm. High TMEM92 expression was significantly correlated with unfavorable prognosis, characterizing by immune resistance. A nomogram model and external validation confirmed that TMEM92 was an independent prognostic factor in pancreatic cancer. An elevated tumor mutation burden (TMB), mostly is consistent with commonly mutations of KRAS and TP53, was found in the high TMEM92 group. The predictive role of TMEM92 in immunotherapeutic response was also confirmed by IMvigor210 datasets. In addition, the specific biological roles of TMEM92 in cancer was explored in vitro. The results showed that abnormal overexpression of TMEM92 was significantly associated with the poor survival rate of pancreatic cancer. Moreover, we demonstrated that TMEM92 inhibit tumour immune responses of the anti-PD-1 antibody with PBMC co-culture.
Conclusion: The current study explored for the first time the immune-resistance phenotype of pancreatic cancer and identified TMEM92 as an innovative marker in predicting clinical outcomes and immunotherapeutic efficacy. These findings not only help to recognize high-risk and immune-resistance population which could be supplied targeted prevention, but also provide personalized medical services by intervening TMEM92 function to improve the prognosis of pancreatic cancer. In addition, the biological role of TMEM92 might reveal the potential molecular mechanisms of pancreatic cancer and lead to a novel sight for development of a PPPM approach for pancreatic cancer management.
Supplementary information: The online version contains supplementary material available at 10.1007/s13167-022-00287-0.
Keywords: Immunotherapy; Pancreatic cancer; Predictive preventive personalized medicine (PPPM); Transmembrane protein 92 (TMEM92); Tumor microenvironment; Tumor-infiltrating immune cells.
© The Author(s), under exclusive licence to European Association for Predictive, Preventive and Personalised Medicine (EPMA) 2022.