Circulating Immune Proteins: Improving the Diagnosis and Clinical Outcome in Advanced Non-Small Cell Lung Cancer.

Immunotherapy has been proven a viable treatment option for non-small cell lung cancer (NSCLC) treatment in patients. However, some patients still do not benefit. Finding new predictive biomarkers for immunocheckpoint inhibitor (ICI) response will improve treatment management in the clinical routine. In this regard, liquid biopsy is a useful and noninvasive alternative to surgical biopsies. In the present study, we evaluated the potential diagnostic, prognostic, and predictive value of seven different soluble mediators involved in immunoregulation. Fifty-two plasma samples from advanced NSCLC treated in first-line with pembrolizumab at baseline (PRE) and at first response assessment (FR) were analyzed. In terms of diagnostic value, our results revealed that sFGL1, sGAL-3, and sGAL-1 allowed for optimal diagnostic efficacy for cancer patients. Additionally, the combination of sFGL1 and sGAL-3 significantly improved diagnostic accuracy. Regarding the predictive value to assess patients' immune response, sCD276 levels at PRE were significantly higher in patients without tumor response (p = 0.035). Moreover, we observed that high levels of sMICB at PRE were associated with absence of clinical benefit (pembrolizumab treatment less than 6 months) (p = 0.049), and high levels of sMICB and sGAL-3 at FR are also related to a lack of clinical benefit (p = 0.027 and p = 0.03, respectively). Finally, in relation to prognosis significance, at PRE and FR, sMICB levels above the 75th percentile are related to poor progression-free survival (PFS) (p = 0.013 and p = 0.023, respectively) and overall survival (OS) (p = 0.001 and p = 0.011, respectively). An increase in sGAL3 levels at FR was associated with worse PFS (p = 0.037). Interestingly, high sGAL-3 at PRE was independently associated with PFS and OS with a hazard ratio (HR) of 2.45 (95% CI 1.14-5.25; p = 0.021) and 4.915 (95% CI 1.89-12.73; p = 0.001). In conclusion, plasma levels of sFGL1, sGAL-3, and sGAL-1 could serve as diagnostic indicators and sMICB, sCD276, and sGAL3 were linked to outcomes, suggesting their potential in assessing NSCLC under pembrolizumab treatment. Our results highlight the value of employing soluble immune biomarkers in advanced lung cancer patients treated with pembrolizumab at first-line.

Overexpression of MRPL19 in predicting poor prognosis and promoting the development of lung adenocarcinoma.

Background: Mitochondrial ribosomal protein L19 (MRPL19) is a member of the mitochondrial ribosomal protein (MRP) family. MRPs have a role in the progression of many cancers. However, the role of MRPL19 in lung adenocarcinoma (LUAD) is yet unknown. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, real-time polymerase chain reaction, and immunohistochemistry (IHC) were used to assess MRPL19 expression and clinical relevance. Gene Expression Profiling Interactive Analysis (GEPIA) and the online Kaplan-Meier (KM) Plotter database were used to determine the prognostic significance. Through use of LinkedOmics, genes that were coexpressed with MRPL19 and its regulators were identified. The biological roles of MRPL19 were investigated through R-implemented packages and RNA interference. The Tumor Immune Estimation Resource (TIMER) was employed to assess the connection between MRPL19 expression and infiltrated immune cells in LUAD. Results: MRPL19 expression in LUAD was upregulated and was correlated with lymph node metastasis, differentiation level, and tumor status. MRPL19 was prognostic and associated with poor prognosis. Functional network analysis revealed that MRPL19 may be associated with the cell cycle, cell adhesion molecules, spliceosome, and T-helper cell differentiation and was regulated by several microRNA and the E2F family. The gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network indicated that MRPL19 was correlated with cancer proliferation signaling pathways. The immune infiltration analysis revealed a correlation between MRPL19 expression and the extent of B cells, CD4+ T cells, and dendritic cells' infiltration in LUAD. Additionally, MRPL19 knockdown in LUAD cells substantially reduced cell growth, migration, and invasion of malignant cells. Conclusions: The poor prognosis and immunological infiltration in LUAD were significantly associated with MRPL19, which may have pro-oncogenic effects on the disease.

Protocol to isolate live single cells while retaining spatial information by combining cell photolabeling and FACS.

Single-cell techniques have revolutionized biology; however, the required sample processing inherently implies the loss of spatial localization. Here, using an approach called photoconversion of areas to dissect micro-environments (PADME), we detail steps to isolate live single cells from a primary breast tumor while retaining spatial information by combining cell photolabeling and FACS (fluorescence-activated cell sorting). These live cells can be subsequently used for myriad techniques, from flow cytometry to single-cell RNA sequencing or other single cell "omics" approach. For complete details on the use and execution of this protocol, please refer to Baldominos et al. (2022).

El sistema inmunitario y la contaminación ambiental son los inductor de los cánceres de pulmón en personas no fumadoras / The immune system and environmental pollution are the inducers of lung cancer in non-smokers

En esta visión de Panorama os presento una idea revolucionaria sobre la formación de tumores enla que está implicada la respuesta inmunitaria. Y me baso en un estudio (Swanton C, ESMO 2022)que posiblemente cambiará la forma en que vemos el cáncer de pulmón en personas que nuncahan fumado. (AU)

Solvent-Free Formation of Cyclodextrin-Based Pseudopolyrotaxanes of Polyethylene Glycol: Kinetic and Structural Aspects.

Pseudopolyrotaxanes (PPRs) are supramolecular structures consisting of macrocycles able to thread on a linear polymer chain in a reversible, non-covalent way, often referred to in the literature as "molecular necklaces". While the synthesis and reaction mechanisms of these structures in solution have been widely described, their solvent-free production has received little attention, despite the advantages that this route may offer. We propose in this work a kinetic mechanism that describes the PPR formation in the solid phase as a process occurring in two consecutive stages. This mechanism has been used to investigate the spontaneous formation of a PPR that occurs when grinding α-Cyclodextrin (α-CD) with polyethylene glycol (PEG). In the threading stage, the inclusion of the polymer and subsequent release of the water molecules lodged in the cavity of the macrocycle cause vibrational changes that are reflected in the time-dependence of the FTIR-ATR spectra, while the further assembly of PPRs to form crystals produces characteristic reflections in the XRD patterns, due to the channel-like arrangement of CDs, that can be used to track the formation of the adduct in crystalline form. The effects that working variables have on the kinetics of the reaction, such as temperature, feed ratio, molar mass of the polymer and the introduction of an amorphous block in the polymer structure, have been investigated. The rate constants of the threading step increase with the temperature and the activation energy of the process increases at lower proportions of CD to PEG. This is attributed to the lower degree of covering of the polymer chain with CDs that reduces the hydrogen-bonding driven stabilization between adjacent macrocycles. The formation of crystalline PPR, which takes place slowly at room temperature, is markedly promoted at higher temperatures, with lower proportions of CD favoring both the formation and the growth of the crystals. The molar mass of the polymer does not modify the typical channel-like arrangement of packed PPRs but the conversion into crystalline PPR diminishes when using PEG1000 instead of PEG400. At a microscopic level, the crystals arrange into lamellar structures, in the order of hundreds of nm, embedded in an amorphous-like matrix. The introduction of a polypropylene oxide block in the structure of the polymer (Pluronic L62) renders poorer yields and a considerable loss of crystallinity of the product of the reaction. The methodology here proposed can be applied to the general case of inclusion complexes of CDs with drugs in the solid phase, or to multicomponent systems that contain polymers as excipients in pharmaceutical formulations along with CDs.

Lung Cancer and Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Identifying Important Knowledge Gaps for Investigation.

Patients with lung cancer are especially vulnerable to coronavirus disease 2019 (COVID-19) with a greater than sevenfold higher rate of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19, a greater than threefold higher hospitalization rate with high complication rates, and an estimated case fatality rate of more than 30%. The reasons for the increased vulnerability are not known. In addition, beyond the direct impact of the pandemic on morbidity and mortality among patients with lung cancer, COVID-19, with its disruption of patient care, has also resulted in substantial impact on lung cancer screening and treatment/management.COVID-19 vaccines are safe and effective in people with lung cancer. On the basis of the available data, patients with lung cancer should continue their course of cancer treatment and get vaccinated against the SARS-CoV-2 virus. For unknown reasons, some patients with lung cancer mount poor antibody responses to vaccination. Thus, boosting vaccination seems urgently indicated in this subgroup of vulnerable patients with lung cancer. Nevertheless, many unanswered questions regarding vaccination in this population remain, including the magnitude, quality, and duration of antibody response and the role of innate and acquired cellular immunities for clinical protection. Additional important knowledge gaps also remain, including the following: how can we best protect patients with lung cancer from developing COVID-19, including managing care in patient with lung cancer and the home environment of patients with lung cancer; are there clinical/treatment demographics and tumor molecular demographics that affect severity of COVID-19 disease in patients with lung cancer; does anticancer treatment affect antibody production and protection; does SARS-CoV-2 infection affect the development/progression of lung cancer; and are special measures and vaccine strategies needed for patients with lung cancer as viral variants of concern emerge.

Characterization of Circulating T Cell Receptor Repertoire Provides Information about Clinical Outcome after PD-1 Blockade in Advanced Non-Small Cell Lung Cancer Patients.

Despite the success of immunotherapies in lung cancer, development of new biomarkers for patient selection is urgently needed. This study aims to explore minimally invasive approaches to characterize circulating T cell receptor beta chain (TCR-ß) repertoire in a cohort of advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. Peripheral blood samples were obtained at two time points: i) pretreatment (PRE) and ii) first response assessment (FR). Next-generation sequencing (NGS) was used to analyze the hypervariable complementary determining region 3 (CDR3) of TCR-ß chain. Richness, evenness, convergence, and Jaccard similarity indexes plus variable (V) and joining (J)-gene usage were studied. Our results revealed that increased richness during treatment was associated with durable clinical benefit (DCB; p = 0.046), longer progression-free survival (PFS; p = 0.007) and overall survival (OS; p = 0.05). Patients with Jaccard similarity index ≥0.0605 between PRE and FR samples showed improved PFS (p = 0.021). Higher TRBV20-1 PRE usage was associated with DCB (p = 0.027). TRBV20-1 levels ≥9.14% in PRE and ≥9.02% in FR significantly increased PFS (p = 0.025 and p = 0.016) and OS (p = 0.035 and p = 0.018). Overall, analysis of circulating TCR-ß repertoire may provide information about the immune response in anti-PD-1 treated NSCLC patients; in this scenario, it can also offer important information about the clinical outcome.

Analysis of the Gut Microbiota: An Emerging Source of Biomarkers for Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer.

BACKGROUND: The human gut harbors around 1013-1014 microorganisms, collectively referred to as gut microbiota. Recent studies have found that the gut microbiota may have an impact on the interaction between immune regulation and anti-cancer immunotherapies. METHODS: In order to characterize the diversity and composition of commensal microbiota and its relationship with response to immune checkpoint blockade (ICB), 16S ribosomal DNA (rDNA) sequencing was performed on 69 stool samples from advanced non-small cell lung cancer (NSCLC) patients prior to treatment with ICB. RESULTS: The use of antibiotics and ICB-related skin toxicity were significantly associated with reduced gut microbiota diversity. However, antibiotics (ATB) usage was not related to low ICB efficacy. Phascolarctobacterium was enriched in patients with clinical benefit and correlated with prolonged progression-free survival, whereas Dialister was more represented in patients with progressive disease, and its higher relative abundance was associated with reduced progression-free survival and overall survival, with independent prognostic value in multivariate analysis. CONCLUSIONS: Our results corroborate the relation between the baseline gut microbiota composition and ICB clinical outcomes in advanced NSCLC patients, and provide novel potential predictive and prognostic biomarkers for immunotherapy in NSCLC.

dPCR application in liquid biopsies: divide and conquer.

Introduction: Precision medicine is already a reality in oncology, since biomarker-driven therapies have clearly improved patient survival. Furthermore, a new, minimally invasive strategy termed 'liquid biopsy' (LB) has revolutionized the field by allowing comprehensive cancer genomic profiling through the analysis of circulating tumor DNA (ctDNA). However, its detection requires extremely sensitive and efficient technologies. A powerful molecular tool based on the principle of 'divide and conquer' has emerged to solve this problem. Thus, digital PCR (dPCR) allows absolute and accurate quantification of target molecules.Areas covered: In this review we will discuss the fundamentals of dPCR and the most common approaches used for partition of samples and quantification. The advantages and limitations of dPCR will be mentioned in the context of LB in oncology.Expert opinion: In our opinion, dPCR has proven to be one of the most sensitive methods available for LB analysis, albeit some aspects such as its capacity of multiplexing and protocol standardization still require further improvements. Furthermore, the increasing sensitivities and lower costs of next generation sequencing (NGS) methods position dPCR as a confirmatory and complementary technique for NGS results which will likely prove to be very useful for treatment monitoring and assessing minimal residual disease.

Las vacunas de ARNm una nueva forma de generar inmunidad contra SARS-CoV-2 / No disponible

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