Abstract
Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance.
Highlights
Chemotherapy, radiotherapy, and surgery have dominated the cancer treatment field for years and did acquire considerable effects
The highest levels of THY1 were found in the progressive disease (PD) group of PD-1 monoclonal antibody (mAb)-treated lung adenocarcinoma (LUAD) patients. These results provide the fundamental basis for further research of immunotherapy resistance and the discovery of new therapeutic target to refine immune checkpoint inhibitors (ICI) treatments of LUAD patients
Immune-stimulating cells and markers, like Th17, effector-memory and Gamma-delta T cells, and neutrophils, were negatively correlated with the pink module (Figure 4C). These results demonstrated that the pink module is a set of genes that potently correlated with cancer stemness and immunosuppressive characteristics
Summary
Chemotherapy, radiotherapy, and surgery have dominated the cancer treatment field for years and did acquire considerable effects These traditional therapies have noticeable limitations in treating patients with late-stage or metastatic malignant tumors and often cause severe side effects. Based on these gene sets, Miranda et al found pervasive negative associations between cancer cell stemness and anticancer immunity [24] They showed that stemness led to higher intratumoral heterogeneity and restrained antitumor immune response, which result in poor outcome for malignant tumor patients. The highest levels of THY1 were found in the PD group of PD-1 mAb-treated LUAD patients These results provide the fundamental basis for further research of immunotherapy resistance and the discovery of new therapeutic target to refine ICI treatments of LUAD patients
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