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The immune checkpoint molecule V-set Ig domain-containing 4 is an independent prognostic factor for multiple myeloma.

ABSTRACT: Multiple myeloma (MM) remains as an incurable disease, despite recent substantial improvements in treatment. Therefore, development of novel biomarkers for risk stratification and new therapeutic targets are imperative. One of the emerging treatments for MM is the immune checkpoint blockades. V-set Ig domain-containing 4 (VSIG4) is a lately studied B7-related immune checkpoint modulator. We assessed the VSIG4 expression in patients with MM and its prognostic impact. We analyzed 81 bone marrow and 66 extramedullary biopsy samples of MM patients using immunohistochemistry. VSIG4 mRNA expression data from the Multiple Myeloma Genomics Portal (MMGP) were analyzed to validate our results. The overall survival (OS) of the high VSIG4 expression group was significantly poorer than that of the low VSIG4 expression group (p = 0.046). VSIG4 expression was remained statistically significant after adjustment for revised international staging system (rISS) and Mayo stratification algorithm (mSMART) risk classification, respectively (p = 0.019 and 0.017). Corroborating results were also observed on analyses of VSIG4 expression in patients with extramedullary MM and external data from the MMGP. Our results suggest that VSIG4 expression in MM is an independent indicator of poor prognosis, implying a possible therapeutic target for immunotherapy for MM.

SUBMITTER: Roh J

PROVIDER: S-EPMC5601638 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The immune checkpoint molecule V-set Ig domain-containing 4 is an independent prognostic factor for multiple myeloma.

Roh Jin J Jeon Youkyoung Y Lee A-Neum AN Lee Sang Min SM Kim YeonMee Y Sung Chang Ohk CO Park Chan-Jeoung CJ Hong Jung Yong JY Yoon Dok Hyun DH Suh Cheolwon C Huh Jooryung J Choi Inhak I Park Chan-Sik CS

Oncotarget 20170722 35

Multiple myeloma (MM) remains as an incurable disease, despite recent substantial improvements in treatment. Therefore, development of novel biomarkers for risk stratification and new therapeutic targets are imperative. One of the emerging treatments for MM is the immune checkpoint blockades. V-set Ig domain-containing 4 (VSIG4) is a lately studied B7-related immune checkpoint modulator. We assessed the VSIG4 expression in patients with MM and its prognostic impact. We analyzed 81 bone marrow an ...[more]

PMID: 28938542

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Project description:V-domain Ig-containing suppressor of T-cell activation (VISTA) is an immune checkpoint gene that inhibits anti-tumor immune responses. Since most malignant pleural mesotheliomas do not respond to anti-programmed cell death(-ligand)1 (PD-(L)1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) therapy and given the recent finding of The Cancer Genome Atlas Study that pleural mesothelioma displays the highest expression of VISTA among all cancers studied, we examined VISTA expression in a large pleural mesothelioma cohort. VISTA and PD-L1 immunohistochemistry were performed on tissue microarray of immunotherapy-naive pleural mesotheliomas (254 epithelioid, 24 biphasic and 41 sarcomatoid) and ten whole-tissue sections of benign pleura (VISTA only). Percentages of tumor and inflammatory cells with positive staining were assessed. Optimal prognostic cutoff percentages were determined using maximally selected rank statistics. Overall survival was evaluated using Kaplan-Meier methods and Cox proportional hazard analysis. All benign mesothelium expressed VISTA. Eighty-five percent of 319 and 38% of 304 mesotheliomas expressed VISTA and PD-L1 (88% and 33% of epithelioid, 90% and 43% of biphasic, and 42% and 75% of sarcomatoid), respectively. Median VISTA score was significantly higher in epithelioid (50%) (vs. biphasic [20%] and sarcomatoid [0]) (p < 0.001), while median PD-L1 score was significantly higher in sarcomatoid tumors (20%) (vs. biphasic and epithelioid [both 0%]) (p < 0.001). VISTA and PD-L1 were expressed in inflammatory cells in 94% (n = 317) and 24% (n = 303) of mesothelioma, respectively. Optimal prognostic cutoffs for VISTA and PD-L1 were 40% and 30%, respectively. On multivariable analysis, VISTA and PD-L1 expression in mesothelioma were associated with better and worse overall survival (p = 0.001 and p = 0.002), respectively, independent of histology. In a large cohort of mesothelioma, we report frequent expression of VISTA and infrequent expression of PD-L1 with favorable and unfavorable survival correlations, respectively. These findings may explain poor responses to anti-PD-(L)1 immunotherapy and suggest VISTA as a potential novel target in pleural mesothelioma.

Dataset Information

The immune checkpoint molecule V-set Ig domain-containing 4 is an independent prognostic factor for multiple myeloma.

Publications

The immune checkpoint molecule V-set Ig domain-containing 4 is an independent prognostic factor for multiple myeloma.

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