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Epstein-Barr virus-positive gastric cancer [EBV (+) GC] is a distinct GC subtype with unique genetic and epigenetic aberrations. Here, we examined resected GC samples and publicly available microarray data and The Cancer Genome Atlas (TCGA) database to identify the mechanism underlying overexpression of PD-L1 in EBV (+) GC. We found that high levels of PD-L1 overexpression in EBV (+) GC were caused by focal amplification of CD274 . By contrast, relatively high expression of PD-L1 in tumor tissue and infiltrating immune cells correlated with CD8 lymphocyte infiltration and IFN-γ expression via IRF3 activation. Since we reported previously that PD-L1 expression is associated both with the presence of CD8 T cells in the tumor microenvironment and with IFN-γ expression in GC, we examined a database to see whether IFN-γ-associated overexpression of PD-L1 plays a significant role in EBV (+) GC. Immunohistochemical staining showed that expression of the IRF3 signature in clinical GC samples was higher in EBV (+) than in EBV (−) cases. The data presented herein reveal a unique dual mechanism underlying PD-L1 overexpression in EBV (+) GC: high focal amplification of CD274 or IFN-γ-mediated signaling via activation of IRF3.

Despite multidisciplinary treatment for patients with advanced gastric cancer, their prognosis remains poor. Therefore, the development of novel therapeutic strategies is urgently needed, and immunotherapy utilizing anti‐programmed death 1/‐programmed death ligand‐1 mAb is an attractive approach. However, as there is limited information on how programmed death ligand‐1 is upregulated on tumor cells within the tumor microenvironment, we examined the mechanism of programmed death ligand‐1 regulation with a particular focus on interferon gamma in an in vitro setting and in clinical samples. Our in vitro findings showed that interferon gamma upregulated programmed death ligand‐1 expression on solid tumor cells through the JAK‐signal transducer and activator of transcription pathway, and impaired the cytotoxicity of tumor antigen‐specific CTL against tumor cells. Following treatment of cells with anti‐programmed death ligand‐1 mAb after interferon gamma‐pre‐treatment, the reduced anti‐tumor CTL activity by interferon gamma reached a higher level than the non‐treatment control targets. In contrast, programmed death ligand‐1 expression on tumor cells also significantly correlated with epithelial‐mesenchymal transition phenotype in a panel of solid tumor cells. In clinical gastric cancer samples, tumor membrane programmed death ligand‐1 expression significantly positively correlated with the presence of CD8‐positive T cells in the stroma and interferon gamma expression in the tumor. The results suggest that gastric cancer patients with high CD8‐positive T‐cell infiltration may be more responsive to anti‐programmed death 1/‐programmed death ligand‐1 mAb therapy. PD‐L1 levels significantly correlated with CD8 (stroma) levels (P = .018), but not with CD3 nor CD4 in tumor/stroma in gastric cancer. Furthermore, PD‐L1 levels also significantly positively correlated with tumor IFN‐γ levels. The results suggests that upregulation of PD‐L1 may result from increased IFN‐γ production by CTLs which migrate to the tumor during immune activation.

The authors report a new type of genetic alteration in lung adenocarcinoma. Fusions of KIF5B with RET kinase are found in 1–2% of lung cancer patients, segregate from other known alterations and can potentially be targeted using RET kinase inhibitors. We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1–2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR , KRAS , HER2 and ALK , and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.

BackgroundSeveral articles have recently reported that certain colon microbiota can improve the efficacy of cancer immunotherapy. To develop new treatment strategies, including immunotherapy for colorectal cancer (CRC), we evaluated the correlations between subpopulations of tumor-infiltrating immune cells (TIICs) and intestinal microbiota in CRC.MethodsFresh surgically resected specimens, formalin-fixed paraffin-embedded whole tissue samples, and stool samples were collected. TIICs including Tregs, Th17 cells and tumor-associated macrophages (TAMs) in the surgically resected specimens were analyzed using flow cytometry. FOXp3, CD8, CD163, and phosphorylated-STAT1-positive TIICs in the whole tissue samples were analyzed using IHC, and intestinal microbiota in the stool samples was analyzed using 16S metagenome sequencing. TIICs subpopulations in the normal mucosa and tumor samples were evaluated, and the correlations between the TIIC subpopulations and intestinal microbiota were analyzed.ResultsFOXp3lowCD45RA+ Tregs were significantly reduced (p = 0.02), FOXp3lowCD45RA− Tregs were significantly increased (p = 0.006), and M1 TAMs were significantly reduced in the tumor samples (p = 0.03). Bacteroides (phylum Bacteroidetes) and Faecalibacterium (phylum Firmicutes) were increased in the patients with high numbers of Tregs and clearly high distribution of FOXp3highCD45RA− Tregs, which are the effector Tregs. Faecalibacterium, Ruminococcaceae, Eubacterium (phylum Firmicutes), and Bacteroides were increased in patients with a high distribution of M1 TAMs.ConclusionsThe findings of the present study indicate that immune responses to tumors are suppressed in the tumor microenvironment of CRC depending on the increment of Tregs and the reduction of M1 TAMs and that intestinal microbiota might be involved in immunosuppression.

AT-rich interactive domain 1A ( ARID1A ) functions as a tumor suppressor and several therapeutic targets in ARID1A -mutated cancers are under development. Here, we investigated the prognostic value of ARID1A for gastric cancer and its association with expression of PD-L1 and p53. ARID1A expression was examined by immunohistochemistry and negative expression of ARID1A was detected in 39 (19.5%) of 200 cases in a test cohort and in 40 (18.2%) of 220 cases in a validation cohort. Negative expression of ARID1A was associated with worse overall survival in undifferentiated cases, particularly early-stage cases. Negative expression of ARID1A was detected in 11 (50%) of 22 PD-L1-positive cases and in 68 (17.1%) of 398 PD-L1-negative cases in a combined cohort. Negative expression of ARID1A was detected in 45 (22%) of 205 p53-positive cases and in 34 (15.8%) of 215 p53-negative cases in a combined cohort. In addition, expression of EZH2, a potential synthetic lethal target in ARID1A -mutated tumors, was detected in 79 ARID1A-negative cases. An ARID1A-knockdown gastric cancer cell line was subjected to microarray analysis, but no actionable targets or pathways were identified. The present results indicate that ARID1A may serve as an early-stage prognostic biomarker for undifferentiated gastric cancer.

BackgroundAlthough immunotherapy with immune checkpoint inhibitors (ICIs) has become a standard therapeutic strategy in colorectal cancer (CRC) exhibiting microsatellite instability-high, limited patients benefit from this new approach. To increase the efficacy of ICIs in CRC patients, it is crucial to control the function of immunosuppressive cells in the tumor microenvironment. M2-tumor-associated macrophages (TAMs) are key immunosuppressive cells and promote tumor growth, angiogenesis, and epithelial-mesenchymal transition. In the present study, we focused on the VEGF signaling pathway in M2-TAMs to control their inhibitory function.MethodsWe evaluated the population of M2-TAMs, the VEGF receptor 2 (VEGFR2) expression on M2-TAMs, and the correlation between HIF-1α-positive cells and VEGFR2 expression levels on M2-TAMs in CRC using the analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n = 592), the flow cytometry of freshly resected surgical specimens of CRC (n = 20), and the immunofluorescence staining of formalin-fixed paraffin-embedded whole tissue samples of CRC (n = 20). Furthermore, we performed a functional assay of M2 macrophages through the VEGF/VEGFR2 signaling pathway in vitro.ResultsThe population of M2-TAMs and their VEGFR2 expression significantly increased in the tumor compared to the normal mucosa in the CRC patients. HIF1-α-positive cells significantly correlated with the VEGFR2 expression level of M2-TAMs. M2 macrophages induced by cytokines in vitro produced TGF-β1 through the VEGF/VEGFR2 signaling pathway.ConclusionsOur results suggest that anti-VEGFR2 therapy may have therapeutic potential to control the immune inhibitory functions of M2-TAMs in CRC, resulting in enhanced efficacy of immunotherapy with ICIs.

In the present study, we evaluated the mechanisms of programmed death ligand 1 (PD-L1) expression in the breast cancer microenvironment, focusing on the role of interferon-γ (IFN-γ), and the clinical indications for anti-programmed cell death 1 (PD-1) /anti-PD-L1 immunotherapy. We evaluated PD-L1 expression in 4 breast cancer cell lines in the presence of 3 types of inhibitors, as well as IFN-γ. The expression of phosphorylated signal transducer and activator of transcription 1 (p-STAT1), one of the IFN-γ signaling pathway molecules, was analyzed using immunohistochemistry (IHC) in relation to PD-L1 and human leukocyte antigen (HLA) class I expression on cancer cells and tumor-infiltrating CD8-positive T cells in 111 patients with stage II/III breast cancer. Using The Cancer Genome Atlas (TCGA) database, the correlation of the IFN-γ signature with PD-L1 expression was analyzed in breast invasive carcinoma tissues. As a result, the JAK/STAT pathway via IFN-γ was mainly involved in PD-L1 expression in the cell lines examined. IHC analysis revealed that the PD-L1 and HLA class I expression levels were significantly upregulated in the p-STAT1-positive cases. TCGA analysis indicated that the PD-L1 expression and IFN-γ signature exhibited a positive correlation. On the whole, these findings suggest that PD-L1 and HLA class I are co-expressed in p-STAT1-positive breast cancer cells induced by IFN-γ secreted from tumor infiltrating immune cells, and that p-STAT1 expression may be a potential biomarker for patient selection for immunotherapy with anti-PD-1/anti-PD-L1 monoclonal antibodies.

Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8+ TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8+ TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8+ TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8+ TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8+ TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8+ TILs and immune-active TME.

Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8 + T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of CXCL9/10/11 in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC.

Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits an immune-active tumor microenvironment (TME) compared to MMR proficient (pMMR)/microsatellite stable/Epstein-Barr virus-negative [EBV (−)] GC. The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has been considered a key regulator of immune cell activation in the TME. However, its significance in regulating the immune-active TME in dMMR/MSI-H GC remains unclear. Here, we demonstrated that tumor cell-intrinsic cGAS–STING was highly expressed in dMMR GC compared to pMMR/EBV (−) GC. The expression of tumor cell-intrinsic STING was significantly and positively associated with the number of CD8 + tumor-infiltrating lymphocytes in GC. Analysis of TCGA datasets revealed that the expression of interferon-stimulated genes and STING downstream T-cell attracting chemokines was significantly higher in MSI-H GC compared to other subtypes of GC with EBV (−). These results suggest that tumor cell-intrinsic STING signaling plays a key role in activating immune cells in the dMMR/MSI-H GC TME and might serve as a novel biomarker predicting the efficacy of immunotherapy for GC treatment.