Turning up the heat on non-immunoreactive tumors: autophagy influences the immune microenvironment in pancreatic cancer

Abstract

Background: Autophagy regulators play important roles in the occurrence and development of a variety of tumors and are involved in immune regulation and drug resistance. However, the modulatory roles and prognostic value of autophagy regulators in pancreatic cancer have not been identified. Methods: Transcriptomic data and survival information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to construct a risk score model. Important clinical features were analyzed to generate a nomogram. In addition, we used various algorithms, including ssGSEA, CIBERSORT, XCELL, EPIC, TIMER, and QUANTISEQ, to evaluate the roles of autophagy regulators in the pancreatic cancer immune microenvironment. Furthermore, the mutation landscape was compared between different risk groups. Results: Pan cancer analysis indicated that most of the autophagy regulators were upregulated in pancreatic cancer and were correlated with methylation and CNV level. MET, TSC1, and ITGA6 were identified as the prognostic autophagy regulators and used to construct a risk score model. Some critical clinical indicators, such as age, American Joint Committee on Cancer (AJCC) T stage, AJCC N stage, alcohol and sex, were combined with the risk model to establish the nomogram, which may offer clinical guidance. In addition, our study demonstrated that the low score groups exhibited high immune activity and high abundances of various immune cells, including T cells, B cells, and NK cells. Patients with high risk scores exhibited lower half inhibitory concentration (IC50) values for paclitaxel and had downregulated expression profiles of PD1, CTLA4, and LAG3. Mutation investigation indicated that the high risk groups exhibited a higher mutation burden and higher mutation number compared to the low risk groups. additionally, we verified our risk stratification method using cytology and histology data from our center, and the results are satisfactory. Conclusion: We speculated that autophagy regulators have large effects on the prognosis, immune landscape and drug sensitivity of pancreatic cancer. Our model, which combines critical autophagy regulators and clinical indicators, will provide guidance for clinical treatment.