Bronchial Secretory Immunoglobulin A Deficiency Correlates With Airway Inflammation and Progression of Chronic Obstructive Pulmonary Disease

Rationale: Although airway inflammation can persist for years after smoking cessation in patients with chronic obstructive pulmonary disease (COPD), the mechanisms of persistent inflammation are largely unknown

Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy.

BACKGROUND: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker. METHODS: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models. RESULTS: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs. CONCLUSIONS: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy

Lung Cancer in Belgium

1610-162

Molecular determinants of lung cancer progression : functional implications of the Polymeric Immunoglobulin Receptor and the Focal Adhesion Kinase

The central hypothesis supporting the work described here is that lung cancer development and progression is the consequence of the acquisition of multiple genetic alterations including mutations and copy number aberrations, and of the loss of tight regulatory mechanisms maintaining cellular physiological processes such as proliferation, apoptosis, and migration. The discovery of these oncogenic alterations and lost key regulatory proteins or pathways should lead to a better understanding of the disease process, and to novel diagnostic and therapeutic interventions. To test this central hypothesis, we took a dual approach: one gene-centric and the other unbiased high-throughput molecular approach. First, we hypothesized that the loss of the polymeric immunoglobulin receptor (pIgR) expression is an early event in lung cancer development and that the biology of this receptor may be implicated in tumorigenesis. This work stems from observations made in Professor Sibille’s Laboratory looking at the role of pIgR in airway biology, particularly host defense mechanisms in chronic obstructive pulmonary disease where pIgR was found to be downregulated, such as in lung cancer. We made the observation that not only pIgR expression was lost early in lung cancer development but also that restoring its function in cancer cells inhibited cellular proliferation. The mechanisms of this observation are indirect and seem to implicate loss of cellular differentiation, loss of cellular polarization, and epithelial mesenchymal transition. Next, we turned to an unbiased genome-wide approach (as opposed to a gene-centric/candidate-based approach to investigate the role of pIgR) to explore SCLC pathogenesis in an unbiased way by interrogating the cancer genome. We focused on SCLC because of the lack of progress in this devastating disease. We analyzed SCLC primary tumors by array comparative genomic hybridization based on the hypothesis that DNA copy number aberrations would allow the identification of molecular pathways of SCLC progression. This work led to the identification of the focal adhesion pathway derangement in SCLC and to a series of functional and translational studies to establish a role of the focal adhesion kinase (FAK) activation in SCLC adhesion and migration, and to correlate its expression with clinical outcomes. Finally, we undertook a high-throughput proteomic analysis to discover new molecular diagnostic and therapeutic biomarkers of SCLC. The goal was to identify membrane-specific protein biomarkers at the surface of SCLC that could be later developed into molecular imaging strategies or targeted therapies. We therefore analyzed membrane-associated protein extracts from immortalized normal bronchial epithelial, NSCLC, and SCLC cell lines by difference gel electrophoresis. This work is still ongoing but has already led to the discovery of new candidate diagnostic or therapeutic biomarkers. Various high-throughput technologies being used in this work, we also reviewed the scientific literature related to these technologies in lung cancer.(SBIM 3) -- UCL, 201

Targeting Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in -Mutant Non-Small-Cell Lung Cancer.

Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include amplification, C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, and amplifications and and translocations, as well as V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of -mutant NSCLC developing a V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context

Good Tolerance to Full-Dose Crizotinib in a Patient with Anaplastic Lymphoma Receptor Tyrosine Kinase-Rearranged Lung Adenocarcinoma and Preexisting Renal Impairment.

Crizotinib is an approved tyrosine kinase inhibitor in the treatment of advanced-stage non-small-cell lung cancer patients with anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement. Renal dysfunction after crizotinib administration was recently reported, but the physiopathological explanation and the safety in patients with preexisting renal dysfunction are still not clear