Purpose: The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacologic intervention have not been systematically characterized. Experimental Design: Pyroptotic cell death was assessed by immunoblot analysis, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of patients with lung cancer were analyzed using IHC. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models. Results: We showed that diverse small-molecule inhibitors specifically targeting KRAS-, EGFR-, or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by DFNA5), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including KRAS-mutant, EGFR-altered, and ALK-rearranged adenocarcinomas. As a result, cooccurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells, succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models. Conclusions: These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics. Clin Cancer Res; 1–12. ©2018 AACR.

Inflammation involves interactions between various immune cells, inflammatory cells, chemokines and cytokines in pancreatic cancer. Cancer cells as well as surrounding stromal and inflammatory cells establish an inflammatory tumor microenvironment (TME). Inflammation is closely associated with immunity. Meanwhile, immune cells are involved in both inflammation and immune response. Tumor-promoting inflammation and tumor-suppressive immunity are two main characteristics of the tumor microenvironment in pancreatic cancer. Yet, the mechanism of inflammation and immune response in pancreatic cancer development is still unclear due to the dual role of some cytokines and the complicated crosstalk between tumor and stromal components in TME. In this review, we outline the principal cytokines and stromal cells in the pancreatic TME that are involved in the tumor-promoting and immunosuppressive effects of inflammation, and discuss the interaction between inflammation and stromal components in pancreatic cancer progression. Moreover, the clinical approaches based on targeting TME in pancreatic cancer are also summarized. Defining the mechanisms of interplay between inflammation and stromal components will be essential for further development of anti-cancer therapies.

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Background: The gut microbiota and its associated metabolites play a critical role in shaping the systemic immune response and influencing the efficacy of immunotherapy. In this study, patients with extensive-stage small cell lung cancer (ES-SCLC) were included to explore the correlation between gut microbiota and metabolites and immunotherapy efficacy in patients with ES-SCLC. Methods: Pre- and post-treatment, we collected stool samples from 49 ES-SCLC patients treated with an anti-programmed death-ligand 1 (PD-L1) antibody. We then applied 16S ribosomal RNA (rRNA) sequencing and liquid chromatography-mass spectrometry (LC-MS) non-targeted metabolomics technology. Subsequently, the gut microbiota and metabolites were identified and classified. Results: The results showed no statistical difference in gut microbiota alpha and beta diversity between the responder (R) and non-responder (NR) patients at baseline. However, the alpha diversity of the R patients was significantly higher than that of the NR patients after treatment. There were also differences in the microbiome composition at the baseline and post-treatment. Notably, after treatment, Faecalibacterium, Clostridium_sensu_stricto_1, and [Ruminococcus]_torques were enriched in the R group, while Dubosiella, coriobacteriaceae_UCG-002 was enriched in the NR group. The non-targeted metabolomics results also indicated that short-chain fatty acids (SCFAs) were up-regulated in the R group after treatment. More, differential metabolites were enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including the PD-L1 expression and programmed death 1 (PD-1) checkpoint pathway in cancer. Conclusions: These findings are anticipated to provide novel markers for predicting the efficacy of immune checkpoint inhibitors (ICIs) in patients with ES-SCLC, and offer new directions for further research on molecular mechanisms.