Expression of the immune checkpoint molecule V-set immunoglobulin domain-containing 4 is associated with poor prognosis
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ORIGINAL ARTICLE
Expression of the immune checkpoint molecule V‑set immunoglobulin domain‑containing 4 is associated with poor prognosis in patients with advanced gastric cancer So‑Woon Kim1,2 · Jin Roh3 · Hye Seung Lee4 · Min‑Hee Ryu5 · Young‑Soo Park1 · Chan‑Sik Park1 Received: 7 February 2020 / Accepted: 3 September 2020 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2020
Abstract Background Recent clinical studies on immune checkpoint (IC) inhibitors in the context of advanced gastric cancer (AGC) have failed to show significant survival benefits but have suggested the possible role of IC inhibitors in anti-AGC immunity. Considering the low efficacy of targeted drugs in AGC, there is an urgent need for the discovery of new targets for the development of immunotherapeutics and prognostic markers for patient selection. This study aimed to investigate the expression of a new IC molecule, V-set Ig domain-containing 4 (VSIG4), and its clinical significance in AGC and other major cancers. Methods We analyzed the expression of VSIG4 and its correlation with survival in various carcinomas, including 882 surgically resected samples from patients with stage II–III AGC (two academic hospitals). Results VSIG4 positivity in AGC was significantly associated with overall survival (OS; Hazard ratio (HR) = 2.661, 95% confidence interval [CI] = 2.012–3.519, P 38 CD163-positive macrophages/HPF.
Advanced gastric cancer subgroupings The study cohort was classified into five molecular subtypes based on the microsatellite instability (MSI) and EBV-status and the expression of E-cadherin and p53 proteins, as previously described [24]. Five subtypes were identified: cluster 1 (EBV-positive tumors), cluster 2 (MSI-High), cluster 3 (aberrant E-cadherin expression), cluster 4 (aberrant p53 expression), and cluster 5 (normal p53 expression) (Supplementary Materials).
Digital image analysis Quantitative image analysis was used to reduce investigator-dependent errors. For quantitative analysis, digital slide images were obtained from the same IHC slides using the discovery set with a Pannoramic 250 Flash III (3DHistech, Hungary) and analyzed using CellProfiler v2.2.0 [25] (Supplementary Materials). VSIG4 expression was also found to be positive based on the staining intensity and proportion. The H-score was calculated, and a cutoff value of 175 was determined using Cutoff finder.
Results VSIG4 positivity was associated with poor OS and EFS The study aimed to assess VSIG4 expression in patients with advanced gastric cancer and evaluate its prognostic impact. In the discovery set, the median follow-up, as assessed by the Kaplan–Meier method, was 84 months, and 195 of the 485 patients (40.2%) died during follow-up. One hundred seventy-seven of the 485 patients (36.5%) were classified as VSIG4 + , and their median OS was 53.29 months versus 76.46 months for the 308 patients in the VSIG4 – group. Ten cases were showing discernable heterogeneity in H-score among cores. Those cases were subject t
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