Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer

Abstract

Rationale: Siglec15 is an emerging target for normalization cancer immunotherapy. However, pan-cancer anti-Siglec15 treatment is not yet validated and the potential role of Siglec15 in bladder cancer (BLCA) remains elusive. Methods: We comprehensively evaluated the expression pattern and immunological role of Siglec15 using pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas. We then systematically correlated Siglec15 with immunological characteristics in the BLCA tumor microenvironment (TME), including immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T cell inflamed score. We also analyzed the role of Siglec15 in predicting the molecular subtype and the response to several treatment options in BLCA. Our results were validated in several public cohorts as well as our BLCA tumor microarray cohort, the Xiangya cohort. We developed an immune risk score (IRS), validated it, and tested its ability to predict the prognosis and response to cancer immunotherapy. Results: We found that Siglec15 was specifically overexpressed in the TME of various cancers. We hypothesize that Siglec15 designs a non-inflamed TME in BLCA based on the evidence that Siglec15 negatively correlated with immunomodulators, TIICs, cancer immunity cycles, immune checkpoints, and T cell inflamed score. Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression. High Siglec15 levels indicated a luminal subtype of BLCA characterized by lower immune infiltration, lower response to cancer immunotherapy and neoadjuvant chemotherapy, but higher response to anti-angiogenic therapy and targeted therapies such as blocking Siglec15, β-catenin, PPAR-γ, and FGFR3 pathways. Notably, a combination of anti-Siglec15 and cancer immunotherapy may be a more effective strategy than monotherapy. IRS can accurately predict the prognosis and response to cancer immunotherapy. Conclusions: Anti-Siglec15 immunotherapy might be suitable for BLCA treatment as Siglec15 correlates with a non-inflamed TME in BLCA. Siglec15 could also predict the molecular subtype and the response to several treatment options.

Ferroptosis‐related gene signature predicts prognosis and immunotherapy in glioma

“…GPX4‐mediated maintenance of redox homeostasis was vital for stimulator‐of‐interferon genes (STING) activation, 56 which plays a critical role in initiating innate immune responses against tumors and microbial infection. In addition, the immune‐related indices shown above are also well‐recognized factors which involve tumor immunotherapy, 35,40,57,58 which also suggests that construction of risk score based on FRGs could well predict glioma immunotherapy.…”

A Poliovirus Receptor (CD155)-Related Risk Signature Predicts the Prognosis of Bladder Cancer

“…Previous studies have employed bioinformatic tools to detect and validate promising molecular targets in cancers, such as Siglec15 in bladder cancer ( 32 ). In our study, a total of 797 BLCA patients from the TCGA and GEO data sets were included to exploit the prognostic significance of risk signature based on PVR -related genes.…”

“…The gene expression levels were calculated using RSEM (v1.2.12). These detailed procedures have been described in our previous study ( 32 ).…”

Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

“…Simultaneously, we obtained the Hallmark gene set from the MSigDB database and quantified the scores of 50 signal pathways using the ssGSEA algorithm to further reveal the differences in biological pathways related to different immunophenotypes. In addition, a set of genes associated with the differentiation of bladder cancer was obtained from the supplementary information by Kamoun et al (27,30).…”