Harnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients

The introduction of immune checkpoint inhibitor (ICI)-based therapy for non-oncogene addicted non-small cell lung cancer (NSCLC) has significantly transformed the treatment landscape of the disease. Inhibitors of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint axis, which were initially considered as a late-line treatment option, gradually became the standard of care as first-line treatment for subgroups of NSCLC patients. However, a significant fraction of patients either fails to respond or progresses after a partial response to ICI treatment. Thus, the identification of mechanisms responsible for innate and acquired resistance to immunotherapy within a rapidly evolving tumor microenvironment (TME) is urgently required, as is the identification of reliable predictive biomarkers beyond PD-L1 expression. The deregulation of the epigenome is a key driver of cancer initiation and progression, and it has also been shown to drive therapeutic resistance. Tumor education of infiltrating myeloid cells towards an immuno-suppressive phenotype as well as induction of T-cell dysfunction in the TME is also driven by epigenome reprogramming. As it stands and, given their dynamic nature, epigenetic changes in cancer and non-cancer cells represent an attractive target to increase immunotherapy activity in NSCLC. Accordingly, clinical trials of combinatorial immuno-epigenetic drug regimens have been associated with tumor response in previously immunotherapy-resistant NSCLC patients irrespective of their PD-L1 status. Moreover, epigenetic signatures might represent valuable theragnostic biomarkers as they can be assayed easily in liquid biopsy and provide multiple layers of information. In this review, we discuss the current knowledge regarding the dysregulated epigenetic mechanisms contributing to immunotherapy resistance in NSCLC. Although the clinical data are still maturing, we highlight the attractive perspective that the synergistic model of immuno-epigenetic strategies might overcome the current limitations of immunotherapy alone and will be translated into durable clinical benefit for a broader NSCLC population

potential role of rictor copy number gain cng as a key biomarker of mtor activity a comprehensive preclinical analysis in squamous cell lung cancer sqlc models

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preliminary results of principe predictors of resistance to immunotherapy with nivolumab niv study in advanced pretreated non small cell lung cancer apnsclc investigating the role of an immune genomic signature igs including jak2 jak3 pias4 ptpn2 stat3 ifnar2 alterations

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Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications

Simple Summary In this manuscript, we offer an integrated molecular analysis of 44 combined large cell neuroendocrine carcinomas (CoLCNECs) in order to deepen the knowledge about these rare histotypes and to clarify their relationship with lung cancers. In the present state of research, molecular studies are still scant, consisting of small and heterogeneous cohorts, and the genomic landscape is poorly characterized. This study shows that CoLCNECs constitute a standalone group of neuroendocrine neoplasm, with three different molecular profiles, two of which overlap with pure LCNEC or adenocarcinoma. CoLCNECs can be considered an independent histologic category with specific genomic and transcriptomic features, different and therefore not comparable to other lung cancers. Indeed, in addition to a histological re-evaluation of lung cancer classification, our study may help to develop a new diagnostic approach for novel and personalized treatments in CoLCNECs. Background: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. Methods: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. Results: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. Conclusions: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC

Comprehensive characterization of intraductal oncocytic papillary neoplasm (IOPN) of the pancreas: a systematic and critical review

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine the most essential features with the systematic review tool. PubMed, SCOPUS, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathological, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) Clinicopathological Features: Male-to-female ratio was 1,5:1. Pancreatic head was the most common site (131/237, 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1/5 of cases (49/237, 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1/pT2 and pN0 (>80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and Molecular Features: The most expressed mucins were MUC5AC (110/112, 98.2%) and MUC6 (78/84, 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (p<0.01). Moreover, fusions involving PRKACA or PRKACB genes were detected in all of 68 cases examined, with PRKACB::ATP1B1 as the most common (27/68 cases, 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (p<0.01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular features. Considering the clinical/prognostic implications, its recognition is essential for pathologists and, ultimately, patients' management

Putative predictors of efficacy for immune checkpoint inhibitors in non-small-cell lung cancer: facing the complexity of the immune system.

In non-small-cell lung cancer (NSCLC) the recent introduction of immunotherapy in daily clinical practice produced a wave of enthusiasm, however, this was rapidly moderated by the evidence that only some patients could experience a relevant clinical benefit. Therefore, a great effort from the scientific community has been dedicated to the identification and validation of reliable biomarkers able to drive the activity of immunotherapeutic agents. Areas covered: This analysis aims to review the main findings about predictive biomarkers for immunotherapy in lung cancer, retracing the history of PD-L1 and focusing on a series of innovative candidates, such as mutational load, immune cell populations and microbiome. Expert commentary: Considering the complexity of the immune system-cancer interactions, the idea of identifying a single biomarker able to drive the activity of different immunotherapeutic agents alone, borrowing the idea of targeted therapy, is likely to represent an unrealistic objective. Nevertheless, the identification of those factors either positively or negatively affecting the response is mandatory in order to recruit the appropriate patients, but also to deeply understand the mechanisms of immune response and improve the clinical benefit deriving from these agents in monotherapy or in a biologically-rationale combination

El reconocimiento del otro: Raíz de una concepción integral e histórica de los derechos humanos

Weight loss and depletion of nutritional status are frequent presentation hallmarks in non-small cell lung cancer (NSCLC). Decline in muscle mass is a major component in weight loss and may have both a prognostic and predictive value for survival and treatment-related toxicities. Recent findings suggest that weight and skeletal muscle mass gain during treatment may represent surrogate markers for outcome in advanced NSCLC patients. Herein we present an in-depth view of the impact of nutritional status derangements on NSCLC patients\u2019 outcome, focusing on lean body mass variations during disease course. We explored the impact of malnutrition with a major attention on novel treatment options. We reviewed molecular, metabolic and immunological mechanisms underlying muscle-wasting condition, which may exhibit a meaningful targeting potential. Incorporating a specialized and accurate body composition assessment into a comprehensive, patient-centered and tailored intervention will facilitate the achievement of nutritional goals and optimal care for lung cancer patients

PD-L1 for selecting non-small-cell lung cancer patients for first-line immuno-chemotherapy combination: A systematic review and meta-analysis

Aim: With the final aim to explore the first-line treatment options for non-small-cell lung cancer (NSCLC) patients, we performed a systematic review and literature-based meta-analysis of available clinical trials exploring immunotherapy in combination versus standard histology-based chemotherapy. Materials &amp; methods: We evaluated interactions according to type of treatment-add-on strategy: immunotherapy in combination versus standard chemotherapy-based regimens. Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were extracted and cumulated. Results: Seven trials (4278 patients) were included. The addition of immunotherapy to standard chemotherapy-based regimens significantly increased OS (HR 0.74; p = 0.001) and PFS (HR 0.61; p &lt; 0.0001) compared with standard-of-care in NSCLC patients in first-line setting. Conclusion: Immunotherapy-based regimens constantly improved OS and PFS compared with chemotherapy in first-line treatment of nononcogene-addicted NSCLC