Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer.

Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood.

Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival.

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors.

Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution.

Cutting-Edge CAR Engineering: Beyond T Cells.

Chimeric antigen receptor (CAR)-T adoptive cell therapy is one of the most promising advanced therapies for the treatment of cancer, with unprecedented outcomes in haematological malignancies. However, it still lacks efficacy in solid tumours, possibly because engineered T cells become inactive within the immunosuppressive tumour microenvironment (TME). In the TME, cells of the myeloid lineage (M) are among the immunosuppressive cell types with the highest tumour infiltration rate.

Systemic CD4 Immunity and PD-L1/PD-1 Blockade Immunotherapy.

PD-L1/PD-1 blockade immunotherapy has changed the therapeutic approaches for the treatment of many cancers. Nevertheless, the mechanisms underlying its efficacy or treatment failure are still unclear. Proficient systemic immunity seems to be a prerequisite for efficacy, as recently shown in patients and in mouse models.

IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet.

Objective: We aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice.

Methods: mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized deletion with tamoxifen. Animals were analyzed at two different ages: ) 13-weeks old young mice, and ) 12-months old middle-aged mice.

Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development.

TRF1 is an essential component of the telomeric protective complex or shelterin. We previously showed that dysfunctional telomeres in alveolar type II (ATII) cells lead to interstitial lung fibrosis. Here, we study the lung pathologies upon telomere dysfunction in fibroblasts, club and basal cells.

Immune Profiling Uncovers Memory T-Cell Responses with a Th17 Signature in Cancer Patients with Previous SARS-CoV-2 Infection Followed by mRNA Vaccination.

It is unclear whether patients with cancer present inherently impaired responses to COVID-19 and vaccination due to their treatments, neoplastic diseases or both. To address this question, immune profiling was performed in three cohorts of healthy donors and oncologic patients: infected with SARS-CoV-2, BNT162b2-vaccinated, and with previous COVID-19 disease and subsequently vaccinated. Cancer patients showed good antibody responses to vaccination, but poor induction of T-cell responses towards the S protein when compared to infection.

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells.

Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor.

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells.

The number of people that are 65 years old or older has been increasing due to the improvement in medicine and public health. However, this trend is not accompanied by an increase in quality of life, and this population is vulnerable to most illnesses, especially to infectious diseases. Vaccination is the best strategy to prevent this fact, but older people present a less efficient response, as their immune system is weaker due mainly to a phenomenon known as immunosenescence.

Circulating Low Density Neutrophils Are Associated with Resistance to First Line Anti-PD1/PDL1 Immunotherapy in Non-Small Cell Lung Cancer.

Single-agent immunotherapy has been widely accepted as frontline treatment for advanced non-small cell lung cancer (NSCLC) with high tumor PD-L1 expression, but most patients do not respond and the mechanisms of resistance are not well known. Several works have highlighted the immunosuppressive activities of myeloid subpopulations, including low-density neutrophils (LDNs), although the context in which these cells play their role is not well defined. We prospectively monitored LDNs in peripheral blood from patients with NSCLC treated with anti-PD-1 immune checkpoint inhibitors (ICIs) as frontline therapy, in a cohort of patients treated with anti-PD1 immunotherapy combined with chemotherapy (CT+IT), and correlated values with outcomes.

Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor.

Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs.

IGF1R acts as a cancer-promoting factor in the tumor microenvironment facilitating lung metastasis implantation and progression.

Given the long-term ineffectiveness of current therapies and late-stage diagnoses, lung cancer is a leading cause of malignant diseases. Tumor progression is influenced by cancer cell interactions with the tumor microenvironment (TME). Insulin-like growth factor 1 receptor (IGF1R) was reported to affect the TME; however, the role of IGF1R in lung TME has not been investigated.

CAR-T Cells for the Treatment of Lung Cancer.

Adoptive cell therapy with genetically modified T lymphocytes that express chimeric antigen receptors (CAR-T) is one of the most promising advanced therapies for the treatment of cancer, with unprecedented outcomes in hematological malignancies. However, the efficacy of CAR-T cells in solid tumors is still very unsatisfactory, because of the strong immunosuppressive tumor microenvironment that hinders immune responses. The development of next-generation personalized CAR-T cells against solid tumors is a clinical necessity.

Correction: Alfaro-Arnedo et al. IGF1R as a Potential Pharmacological Target in Allergic Asthma. 2021, , 912.

In the original article [...

Early differential responses elicited by BRAF in adult mouse models.

The BRAF gene is frequently mutated in cancer. The most common genetic mutation is a single nucleotide transition which gives rise to a constitutively active BRAF kinase (BRAF) which in turn sustains continuous cell proliferation. The study of BRAF murine models has been mainly focused on the role of BRAF in tumor development but little is known on the early molecular impact of BRAF expression in vivo.

IGF1R as a Potential Pharmacological Target in Allergic Asthma.

Background: Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Although Insulin-like growth factor 1 receptor (IGF1R) was found to be involved in asthma, its pharmacological inhibition has not previously been investigated in this pathology. We aimed to determine if therapeutic targeting of IGF1R ameliorates allergic airway inflammation in a murine model of asthma.

Short and dysfunctional telomeres protect from allergen-induced airway inflammation.

Asthma is a chronic inflammatory disease affecting 300 million people worldwide. As telomere shortening is a well-established hallmark of aging and that asthma incidence decreases with age, here we aimed to study the role of short telomeres in asthma pathobiology. To this end, wild-type and telomerase-deficient mice with short telomeres (third-generation (G3 Tert mice)) were challenged with intranasal house dust mite (HDM) extract.

IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis.

Insulin-like growth factor 1 receptor (IGF1R)-mediated signaling pathways modulate important neurophysiological aspects in the central nervous system, including neurogenesis, synaptic plasticity and complex cognitive functions. In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K/Akt and MAPK/ERK1/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old ; male mice in which was conditionally deleted.

Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging.

Short/dysfunctional telomeres are at the origin of idiopathic pulmonary fibrosis (IPF) in patients mutant for telomere maintenance genes. However, it remains unknown whether physiological aging leads to short telomeres in the lung, thus leading to IPF with aging. Here, we find that physiological aging in wild-type mice leads to telomere shortening and a reduced proliferative potential of alveolar type II cells and club cells, increased cellular senescence and DNA damage, increased fibroblast activation and collagen deposits, and impaired lung biophysics, suggestive of a fibrosis-like pathology.

Luminescent Cycloplatinated Complexes with Biologically Relevant Phosphine Ligands: Optical and Cytotoxic Properties.

Two series of neutral luminescent pentafluorophenyl cycloplatinated(II) complexes [Pt(C^N)(CF)L] [C^N = C-deprotonated 2-phenylpyridine (ppy; a), 2-(2,4-difluorophenylpyridine (dfppy; b)] incorporating dimethyl sulfoxide [L = DMSO for 1 (1a reported by us in ref (14) )] or biocompatible phosphine [L = PPhCHCOOH (dpbH; 2), PPhCHCONHCHCOOMe (dpbGlyOMe; 3), P(CHSONa) (TPPTS; 4)] ligands have been prepared and characterized and their optical properties studied. Their cytotoxic activities against tumor A549 (lung carcinoma), HeLa (cervix carcinoma), and nontumor NL-20 (lung epithelium) cell lines, as well as the ability to interact with DNA (plasmid pBR322), were evaluated. Complexes 2 exhibit higher cytotoxicity (IC 3.

Prominent release of lipoxygenase generated mediators in a murine house dust mite-induced asthma model.

The profile of activation of lipid mediator (LM) pathways in asthmatic airway inflammation remains unclear. This experimental study quantified metabolite levels of ω3-, ω6- and ω9-derived polyunsaturated fatty acids in bronchoalveolar lavage fluid (BALF) after 4-weeks of repeated house dust mite (HDM) exposure in a murine (C57BL/6) asthma model. The challenge induced airway hyperresponsiveness, pulmonary eosinophil infiltration, but with low and unchanged mast cell numbers.

Characterization of the acute inflammatory profile and resolution of airway inflammation after Igf1r-gene targeting in a murine model of HDM-induced asthma.

Asthma is a chronic inflammatory disease characterized by bronchial hyperresponsiveness, mucus overproduction and airway remodeling. Notably, we have recently demonstrated that insulin-like growth factor 1 receptor (IGF1R) deficiency in mice attenuates airway hyperresponsiveness and mucus secretion after chronic house dust mite (HDM) exposure. On this basis, inbred C57BL/6 and Igf1r-deficient mice were given HDM extract to study the acute inflammatory profile and implication of Igf1r in acute asthma pathobiology.

Benzothiazole-Based Cycloplatinated Chromophores: Synthetic, Optical, and Biological Studies.

Cycloplatinated complexes based on 2-(4-substituted)benzothiazole ligands of type [Pt(R-PBT-κC,N)Cl(L)] (PBT=2-phenylbenzothiazole; R=Br (1), Me N (2); L=dimethyl sulfoxide (DMSO; a), 1,3,5- triaza-7-phosphaadamantane (PTA; b), triphenylphosphine 3,3',3''-trisulfonate (TPPTS; c)) and [Pt(Br-PBT-κC)Cl(PTA) ] (3) are presented. On the basis of the photophysical data and time-dependent (TD)-DFT calculations (1 a and 2 a), the low-lying transitions (absorption and emission) were associated with ligand-center (LC) charge transfer, with minor metal-to-ligand charge transfer (MLCT), and intraligand charge transfer (ILCT) [Me N-PBT→PBT] excited states, respectively. Simultaneous fluorescence/phosphorescence bands were found in fluid solutions (and also in the solid state for 2 a), which become dominated by triplet emission bands in rigid media at 77 K.

IGF1R deficiency attenuates acute inflammatory response in a bleomycin-induced lung injury mouse model.

IGF1R (Insulin-like Growth Factor 1 Receptor) is a tyrosine kinase with pleiotropic cellular functions. IGF activity maintains human lung homeostasis and is implicated in pulmonary diseases such as cancer, ARDS, COPD, asthma and fibrosis. Here we report that lung transcriptome analysis in mice with a postnatally-induced Igf1r gene deletion showed differentially expressed genes with potentially protective roles related to epigenetics, redox and oxidative stress.