Dataset Information

Biomarkers for immunotherapy in bladder cancer: a moving target.

ABSTRACT: Treatment options for metastatic urothelial carcinoma (mUC) remained relative unchanged over the last 30 years with combination chemotherapy as the mainstay of treatment. Within the last year the landscape for mUC has seismically shifted following the approval of five therapies targeting the programmed cell death protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis. Notably, the anti-PD-1 antibody pembrolizumab demonstrated improved OS relative to chemotherapy in a randomized phase III study for second line treatment of mUC; this level 1 evidence led to approval from the U.S. Food and Drug Administration (FDA). The PD-1 antibody nivolumab also demonstrated an overall survival benefit, in this case in comparison to historical controls. Similarly, antibodies targeting PD-L1 including atezolizumab, durvalumab, and avelumab have now received accelerated approval from the FDA as second line treatments for mUC, with durable response lasting more than 1 year in some patients. Some of these agents are approved in the first line setting as well - based on single-arm phase II studies atezolizumab and pembrolizumab received accelerated approval for first-line treatment of cisplatin ineligible patients. Despite these multiple approvals, the development of clinically useful biomarkers to determine the optimal treatment for patients remains somewhat elusive. In this review, we examine key clinical trial results with anti-PD1/PD-L1 antibodies and discuss progress towards developing novel biomarkers beyond PD-L1 expression.

SUBMITTER: Aggen DH

PROVIDER: S-EPMC5697433 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Biomarkers for immunotherapy in bladder cancer: a moving target.

Aggen David H DH Drake Charles G CG

Journal for immunotherapy of cancer 20171121 1

Treatment options for metastatic urothelial carcinoma (mUC) remained relative unchanged over the last 30 years with combination chemotherapy as the mainstay of treatment. Within the last year the landscape for mUC has seismically shifted following the approval of five therapies targeting the programmed cell death protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis. Notably, the anti-PD-1 antibody pembrolizumab demonstrated improved OS relative to chemotherapy in a randomized phase III stu ...[more]

PMID: 29157296

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Project description:Insulin-like growth factor binding protein-7 (IGFBP7) was recently reported to be a ligand of CD93, a potential target to normalize vasculature and attenuate immunotherapy. However, its role in the tumor microenvironment (TME) and immunotherapy response of bladder cancer (BLCA) remains unclear. We comprehensively evaluated the correlation between IGFBP7 and multiple immunological characteristics of BLCA across The Cancer Genome Atlas (TCGA) and two external cohorts. Importantly, the response of IGFBP7-grouped BLCA patients to immunotherapy was predicted and validated by five real-word immunotherapy cohorts. Finally, we developed an IGFBP7-based immune risk model validated by five independent cohorts. IGFBP7 modulated the TME across pan-caners. In BLCA, high expression of IGFBP7 was correlated with more aggressive clinical features. IGFBP7 was positively associated with immunomodulators and promoted tumor-infiltrating lymphocyte trafficking into the tumor microenvironment. However, T cells recognition and tumor cell killing were lower in the high-IGFBP7 group. In addition, high expression of IGFBP7 displayed lower enrichment scores for most pro-immunotherapy pathways. Clinical data from IMvigor210 and GSE176307 indicated that IGFBP7 negatively correlated with the BLCA immunotherapy response. The same trend was also observed in a renal cell carcinoma (RCC) cohort and two melanoma cohorts. Notably, urothelial and luminal differentiation were less frequently observed in the high-IGFBP7 group, while neuroendocrine differentiation was more frequently observed. Mechanistically, high IGFBP7 was associated with an enriched hypoxia pathway and higher expression of key genes in ERBB therapy and antiangiogenic therapy. Furthermore, our IGFBP7-based immune risk model was able to predict the prognosis and response to immunotherapy with good accuracy (5-year AUC = 0.734). Overall, IGFBP7 plays a critical role in the immunoregulation and TME of BLCA and may serve as a novel potential target for combination treatment with immunotherapy for BLCA.

Project description:Bladder cancer is known to be the most common malignant tumor in the urinary system and has a poor prognosis; thus, new targets for drug treatment are urgently needed. Pyroptosis is defined as programmed cell death in the inflammatory form mediated by the gasdermin protein. It has therapeutic potential due to the synergistic effect of radiotherapy and chemotherapy, can reverse chemotherapy resistance, is able to regulate the body environment to alter tumor metabolism, and may enhance the response rate of the immune checkpoint inhibitor. Accordingly, this study attempted to explore the role of pyroptosis in bladder cancer. A prognostic model based on five pyroptosis-related genes was constructed by conducting univariate Cox survival and LASSO regression analyses using The Cancer Genome Atlas (TCGA) cohort. Patients were divided into high- and low-risk groups according to the median risk score, with all five PRGs having downregulated expression in the high-risk group. The high-risk group was shown to have a worse prognosis than the low-risk group, and survival differences between the two groups were then validated in the Gene Expression Omnibus (GEO) cohort. Moreover, the ROC curves demonstrated the model's moderate predictive ability. The univariate and multivariate Cox regression analyses indicated that risk scores were found to serve as an independent prognosis factor for OS in bladder cancer patients. In addition, the high-risk group was observed to be associated with advanced N and TNM stages. A nomogram combining risk scores and clinical features was then established, with the ROC curve indicating that the AUC of TCGA training cohort in 3 and 5 years was 0.789 and 0.775, respectively. The calibration curve exhibited a high consistency between the actual survival rate and the predicted rate. Furthermore, the GO and KEGG analyses found that antigen processing and presentation of exogenous antigen, exogenous peptide antigen, and peptide antigen were enriched in the low-risk group. A higher abundance of tumor-infiltrating immune cells and additional active immune pathways were also noted in the low-risk group. In addition, immunotherapy biomarkers, including TMB, PD1, PD-L1, CTLA4, and LAG3, were shown to have higher levels in the low-risk group. Therefore, patients in the low-risk group may be potential responders to immune checkpoint inhibitors.

Dataset Information

Biomarkers for immunotherapy in bladder cancer: a moving target.

Publications

Biomarkers for immunotherapy in bladder cancer: a moving target.

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