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Malignant pleural mesothelioma (MPM) is an aggressive solid cancer with a poor prognosis, whereas coxsackievirus A11 (CVA11) is a potential oncolytic virus for cancer treatment. We here investigated the oncolytic activity of CVA11 with human MPM cell lines. CVA11 infection was cytotoxic in all six MPM cell lines examined and showed no or minimal cytotoxicity toward normal human normal cell lines. MPM cells with a higher surface level of intercellular adhesion molecule‐1 (ICAM‐1) expression tended to be more susceptible to CVA11‐induced cytotoxicity, and a neutralizing antibody to ICAM‐1 attenuated such cytotoxicity. CVA11 infection activated signaling by Akt and extracellular signal‐regulated kinase (ERK) pathways, and inhibitors of such signaling also abrogated CVA11‐mediated cytotoxicity. Furthermore, CVA11 infection‐triggered multiple modes of tumor cell death including apoptosis, pyroptosis, and necroptosis, and such death was accompanied by the release or exposure of the proinflammatory cytokine interleukin‐1β and damage‐associated molecular patterns such as calreticulin, high‐mobility group box‐1, annexin A1, and heat shock protein 70, which are hallmarks of immunogenic cell death. Notably, in vivo treatment of human MPM xenografts with intratumoral CVA11 injection resulted in significant suppression of tumor growth in SCID mice, and all mice infected with CVA11 showed no significant change in body weight. Our findings collectively suggest that the oncolytic activity of CVA11 for MPM is dependent on ICAM‐1 as a virus receptor, as well as on Akt and ERK signaling, and that oncolytic virotherapy with CVA11 is a promising treatment modality with immunostimulatory activity for human MPM. The authors found that coxsackievirus A11 (CVA11) infection exhibited a marked oncolytic activity in multiple human malignant pleural mesothelioma cell lines in vitro, and that serial intratumoral CVA11 injections into mesothelioma xenografts resulted in significant suppression of tumor growth in SCID mice with tolerability. The authors successfully identified ICAM‐1 as a receptor for CVA11 infection. CVA11 infection‐triggered cytotoxicity was partially dependent on MEK/ERK and PI3K/Akt signaling pathways and manifested multimodal immunogenic cell death with proinflammatory cytokine and DAMPs.

Treatment with immune checkpoint inhibitors induces a durable response in some patients with non‐small‐cell lung cancer, but eventually gives rise to drug resistance. Upregulation of CD155 expression is implicated as one mechanism of resistance to programmed death receptor‐1 (PD‐1)/PD‐1 ligand (PD‐L1) inhibitors, and it is therefore important to characterize the mechanisms underlying regulation of CD155 expression in tumor cells. The aim of this study was to identify microRNAs (miRNAs) that might regulate CD155 expression at the posttranscriptional level in lung cancer. Comprehensive miRNA screening with target prediction programs and a dual‐luciferase reporter assay identified miR‐346, miR‐328‐3p, miR‐326, and miR‐330‐5p as miRNAs that bind to the 3′‐UTR of CD155 mRNA. Forced expression of these miRNAs suppressed CD155 expression in lung cancer cell lines. Immunohistochemical staining of CD155 in tissue specimens from 57 patients with lung adenocarcinoma revealed the median tumor proportion score for CD155 to be 68%. The abundance of miR‐326 in these specimens with a low level of CD155 expression was significantly greater than in specimens with a high level ( p  < 0.005). Our results thus suggest that miR‐326 negatively regulates CD155 expression in lung adenocarcinoma and might therefore play a role in the development of resistance to PD‐1/PD‐L1 inhibitors.

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we undertook genomic profiling of IPF‐associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF‐associated non‐small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next‐generation sequencing with a panel that targets 161 cancer‐related genes. Somatic genetic alterations were frequently identified in TP53 (n = 6, 35.3%) and PIK3CA (n = 5, 29.4%) genes in tumor samples as well as in EGFR (n = 7, 46.7%), PIK3CA (n = 5, 33.3%), ERBB3 (n = 4, 26.7%), and KDR (n = 4, 26.7%) in IPF samples. Genes related to the RAS‐RAF signaling pathway were also frequently altered in tumor (n = 7, 41.2%) and IPF (n = 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 vs 90, respectively). However, only 6 of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF‐associated lung cancer, and the RAS‐RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF‐associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF. The genetic basis of idiopathic pulmonary fibrosis‐associated lung cancer remains largely unknown. We show that somatic alterations were frequently identified in fibrosing lung tissue as much as that in tumor tissue, and that genes related to the RAS‐RAF signaling pathway were frequently altered in both specimens. These findings can provide a basis for the development of targeted drugs for such tumors.

The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.

EGFR tyrosine kinase inhibitors (TKIs) are effective against EGFR -mutated lung cancer, but tumors eventually develop resistance to these drugs. Although TP53 gain-of-function (GOF) mutations promote carcinogenesis, their effect on EGFR-TKI efficacy has remained unclear. We here established EGFR -mutated lung cancer cell lines that express wild-type (WT) or various mutant p53 proteins with CRISPR-Cas9 technology and found that TP53 -GOF mutations promote early development of resistance to the EGFR-TKI osimertinib associated with sustained activation of ERK and expression of c-Myc. Gene expression analysis revealed that osimertinib activates TNF-α–NF-κB signaling specifically in TP53 -GOF mutant cells. In such cells, osimertinib promoted interaction of p53 with the NF-κB subunit p65, translocation of the resulting complex to the nucleus and its binding to the TNF promoter, and TNF-α production. Concurrent treatment of TP53 -GOF mutant cells with the TNF-α inhibitor infliximab suppressed acquisition of osimertinib resistance as well as restored osimertinib sensitivity in resistant cells in association with attenuation of ERK activation and c-Myc expression. Our findings indicate that induction of TNF-α expression by osimertinib in TP53 -GOF mutant cells contributes to the early development of osimertinib resistance, and that TNF-α inhibition may therefore be an effective strategy to overcome such resistance in EGFR -mutant lung cancer with TP53 -GOF mutations.

Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P  = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P  = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance‐conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non‐small‐cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next‐generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M—including copy number gain of NRAS or MET—were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression‐free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR‐TKI treatment. Quantitation of T790M in plasma is a clinically relevant approach to determine the T790M status of tumors.

Programmed cell death-ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC). We performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β to elucidate its induction of PD-L1 on NSCLC cells. The IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ. Our study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells activation of MAPK signaling, with the IL-1β-MAPK axis being a promising therapeutic target for attenuation of PD-L1-mediated suppression of antitumor immunity.

Background Despite an initial favorable response of EGFR -mutant non–small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance to this drug inevitably develops. Whereas genetic mechanisms for such acquired resistance have been identified, the molecular mediators of resistance induction have remained unclear. Methods To identify factors that mediate induction of osimertinib resistance, we studied clinical samples from individuals with EGFR -mutant NSCLC as well as cell lines including PC-9 and H1975. Methods adopted included transcriptomics analysis and immunohistochemistry of pretreatment NSCLC specimens, spatial transcriptomics analysis, a cell viability assay, immunofluorescence and quantitative PCR analysis, RNA sequencing, immunoblot analysis, comprehensive proteomics analysis by mass spectrometry, co-immunoprecipitation and proximity ligation assays, and a mouse xenograft tumor model. Results Transcriptomics analysis of pretreatment clinical specimens identified IFITM3 (interferon-induced transmembrane protein 3) as a gene specifically upregulated in patients with a poor response to osimertinib treatment. Immunohistochemistry confirmed that patients with IFITM3-positive tumors experienced a shorter progression-free survival on osimertinib treatment. Spatial transcriptomics and other analyses further revealed that IFITM3 expression in tumor cells was increased in response to cytokines derived from the tumor microenvironment (TME) during osimertinib treatment. IFITM3 was found to promote the development of osimertinib resistance in NSCLC cell lines through interaction with MET and activation of the AKT signaling pathway. Furthermore, combined treatment with a MET inhibitor suppressed the development of osimertinib resistance in a mouse xenograft tumor model. Conclusions Our findings reveal that upregulation of IFITM3 driven by TME cytokines represents a previously unrecognized mechanism of osimertinib resistance, and they suggest that targeting of the IFITM3-MET axis may improve EGFR-TKI treatment outcome for EGFR -mutant NSCLC.

Background Driver gene alterations are increasingly being identified, and multiplex genetic tests have become essential for determining the optimal treatment method for advanced non‐small cell lung cancer (NSCLC). Next‐generation sequencing (NGS) enables the simultaneous detection of multiple driver gene alterations using nucleic acids extracted from tumor tissue samples. However, obtaining sufficient tumor tissue volume is challenging, and inadequate formalin fixation can lead to the failure of NGS analysis. Malignant pleural effusions can be collected using a simple, minimally invasive technique; however, it remains uncertain whether pleural fluid is a suitable source for detecting driver gene alterations using NGS. This retrospective observational study examined the suitability of fresh‐frozen pleural fluid pellets for NGS in clinical practice. Methods Patients with NSCLC whose frozen pleural fluid pellets were analyzed using the Oncomine Dx Target Test Multi‐CDx System between June 2019 and February 2024 were included in the study. The primary endpoint was the success rate of driver gene analysis. Results In total, 26 patients were enrolled. The success rate for testing alterations in driver genes was 92.3% (24/26), and the detection rate of targetable driver gene alterations was 53.8% (14/26). The median turnaround time from sample submission to result confirmation was 10 days (range 7–19 days). Conclusion Our findings indicate that frozen pleural fluid pellets are suitable for NGS‐based driver gene testing in patients with advanced NSCLC. This approach provides a practical alternative for multigene testing when sufficient tissue is not available. This study demonstrated a high success rate of driver gene testing using the Oncomine Dx Target Test (ODxTT) on fresh‐frozen pleural fluid pellets from patients with NSCLC.