Background Durable efficacy of immune checkpoint blockade (ICB) occurred in a small number of patients with metastatic gastric cancer (mGC) and the determinant biomarker of response to ICB remains unclear. Methods We developed an open-source TMEscore R package, to quantify the tumor microenvironment (TME) to aid in addressing this dilemma. Two advanced gastric cancer cohorts (RNAseq, N=45 and NanoString, N=48) and other advanced cancer (N=534) treated with ICB were leveraged to investigate the predictive value of TMEscore. Simultaneously, multi-omics data from The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) and Asian Cancer Research Group (ACRG) were interrogated for underlying mechanisms. Results The predictive capacity of TMEscore was corroborated in patient with mGC cohorts treated with pembrolizumab in a prospective phase 2 clinical trial (NCT02589496, N=45, area under the curve (AUC)=0.891). Notably, TMEscore, which has a larger AUC than programmed death-ligand 1 combined positive score, tumor mutation burden, microsatellite instability, and Epstein-Barr virus, was also validated in the multicenter advanced gastric cancer cohort using NanoString technology (N=48, AUC=0.877). Exploration of the intrinsic mechanisms of TMEscore with TCGA and ACRG multi-omics data identified TME pertinent mechanisms including mutations, metabolism pathways, and epigenetic features. Conclusions Current study highlighted the promising predictive value of TMEscore for patients with mGC. Exploration of TME in multi-omics gastric cancer data may provide the impetus for precision immunotherapy.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RICTOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. Significance: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility. This article is highlighted in the In This Issue feature, p. 1325

Chemotherapy is ubiquitous in first-line treatment of advanced gastric cancer, yet responses are heterogeneous, and little is known about mediators of chemotherapy response. To move forward, an understanding of the effects of standard chemotherapy on the tumor–immune microenvironment (TME) is needed. Coupling whole-exome sequencing, bulk RNA and single-cell transcriptomics from paired pretreatment and on-treatment samples in treatment-naïve patients with HER2-positive and HER2-negative gastric cancer, we define features associated with response to platinum-based chemotherapy. Response was associated with on-treatment TME remodeling including natural killer (NK) cell recruitment, decreased tumor-associated macrophages, M1-macrophage repolarization, and increased effector T-cell infiltration. Among chemotherapy nonresponders, we observed low/absent PD-L1 expression or modulation, on-treatment increases in Wnt signaling, B-cell infiltration, and LAG3-expressing T cells coupled to an exodus of dendritic cells. We did not observe significant genomic changes in early on-treatment sampling. We provide a map of on-treatment TME modulation with standard chemotherapy and nominate candidate future approaches. Significance: Using paired pretreatment and on-treatment samples during standard first-line chemotherapy, we identify chemotherapy-induced NK-cell infiltration, macrophage repolarization, and increased antigen presentation among responders. Increased LAG3 expression and decreased dendritic cell abundance were seen in nonresponders, emphasizing remodeling of the TME during chemotherapy response and resistance. This article is highlighted in the In This Issue feature, p. 873

Epstein-Barr virus (EBV) is a ubiquitous γ-1 herpes virus usually acquired during childhood via salivary transmission, which establishes a life-long persistent infection of B cells in over 90% of adults.¹ x 1 Young, L.S. and Rickinson, A.B. Epstein-Barr virus: 40 years on. Nature reviews. 2004; 4: 757–768 Crossref | Scopus (1236) | Google Scholar See all References Like all herpes viruses, EBV has both a lytic and a latent phase, characterized by the sequential expression of different genes.² x 2 Deyrup, A.T. Epstein-Barr virus-associated epithelial and mesenchymal neoplasms. Human pathology. 2008; 39: 473–483 Abstract | Full Text | Full Text PDF | PubMed | Scopus (58) | Google Scholar See all References EBV infection is implicated in the etiology of B and T lymphomas, natural killer cell malignancies, nasopharyngeal undifferentiated carcinomas, and a subset of smooth muscle tumors.³ x 3 Delecluse, H.J., Feederle, R., O'Sullivan, B. et al. Epstein Barr virus-associated tumours: an update for the attention of the working pathologist. J Clin Pathol. 2007; 60: 1358–1364 Crossref | PubMed | Scopus (84) | Google Scholar See all References