Characterization of Platelet Function-Related Gene Predicting Survival and Immunotherapy Efficacy in Gastric Cancer

Abstract

Immunotherapy is widely used to treat various cancers, but patients with gastric cancer (GC), which has a high mortality rate, benefit relatively less from this therapy. Platelets are closely related to GC progression and metastasis. This study aimed to find novel potential biomarkers related to platelet function to predict GC and immunotherapy efficacy. First, based on platelet activation, signaling, and aggregation (abbreviation: function)-related genes (PFRGs), we used the least absolute shrinkage and selection operator (Lasso) regression method to construct a platelet-function-related genes prognostic score (PFRGPS). PRFGPS was verified in three independent external datasets (GSE26901, GSE15459, and GSE84437) for its robustness and strong prediction performance. Our results demonstrate that PRFGPS is an independent prognostic indicator for predicting overall survival in patients with GC. In addition, prognosis, potential pathogenesis mechanisms, and the response to immunotherapy were defined via gene set enrichment analysis, tumor mutational burden, tumor microenvironment, tumor immune dysfunction and exclusion (TIDE), microsatellite instability, and immune checkpoint inhibitors. We found that the high-PRFGPS subgroup had a cancer-friendly immune microenvironment, a high TIDE score, a low tumor mutational burden, and relatively low microsatellite instability. In the immunophenoscore model, the therapeutic effect on anti-PD-1 and anti-CTLA-4 in the high-PRFGPS subgroup was relatively low. In conclusion, PRFGPS could be used as a reference index for GC prognosis to develop more successful immunotherapy strategies.

Development and experimental validation of an M2 macrophage and platelet‐associated gene signature to predict prognosis and immunotherapy sensitivity in bladder cancer

“…It has been claimed that platelets can be domesticated by tumor cells and thus, their genomic profiles and biological processes are altered 15 . In turn, platelets could also affect tumor development and immune escape 16,17 . Platelets are reportedly capable of regulating the repolarization of macrophages, but there is some debate about this (see above) 11,13 .…”

“… 15 In turn, platelets could also affect tumor development and immune escape. 16 , 17 Platelets are reportedly capable of regulating the repolarization of macrophages, but there is some debate about this (see above). 11 , 13 Specifically, platelets modulate the secretion of cytokines like IL‐10 and TGFB in regulatory T cells to induce polarization of M2 macrophages in pulmonary infections, 18 the products from platelets enhance IL‐4‐mediated M2 polarization through PGE2 in atherosclerosis, 19 and platelets mediate macrophage polarization to an inflammatory M1‐like state by inducing Socs3 expression in atherosclerosis.…”

Gastric cancer fibroblasts affect the effect of immunotherapy and patient prognosis by inducing micro-vascular production

“…However, high SPARC expression is associated with a good prognosis in diffuse large B-cell lymphoma ( 40 ). SPARC is negatively associated with GC prognosis by regulating platelet activation ( 41 ). Meanwhile, EDNRA is an endothelin-1 receptor expressed in many malignancies that is closely associated with cell proliferation, invasion, migration, metastasis, and drug resistance ( 42 , 43 ).…”