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

Role of Focal Adhesion Kinase in the invasive phenotype of small-cell lung cancer

Small-cell lung cancer (SCLC) is a devastating illness with frequent metastases and poor survival. The molecular steps leading to SCLC development and progression are still poorly understood and this has translated into the absence of effective targeted therapies and a five-year overall survival as low as 5%. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase localized at sites of focal adhesions and playing an important role in signal transduction pathways initiated by integrins and G-protein-coupled-receptors. It is overexpressed in many cancers and contributes to cancer progression through a central role in cell adhesion, migration, invasion, survival, and growth, which are highly relevant in SCLC, known to be very aggressive. Since FAK has been poorly studied in SCLC, we decided to investigate it at the functional level in this cancer. We found that FAK was strongly expressed and activated in primary SCLC tumors compared to non-small-cell lung cancer and normal lung. Moreover, inhibition of FAK activity in SCLC cell lines where FAK is overexpressed and constitutively activated decreased FAK phosphorylation (Tyr397) and resulted in antitumoral effects. Inhibition of FAK activity significantly decreased cell proliferation, induced cell cycle arrest in G2/M phases, decreased DNA synthesis, increased apoptosis, and decreased motility as well as invasion in SCLC cell lines. Altogether, this work demonstrates that FAK activation plays a key role in the invasive behaviour of SCLC and suggests that FAK-targeted therapeutic strategies should be evaluated in clinical trials with the hope of reducing mortality from SCLC.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 202

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

Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC

Effects of exercise therapy in cancer patients undergoing radiotherapy treatment: a narrative review

Despite its beneficial effects, radiotherapy (RT) still results in a range of side effects that negatively impact quality of life of patients. Exercise has been shown to counteract the side effects induced by cancer treatment. This narrative review aims to provide an up-to-date review of the effects of an exercise intervention in cancer patients during RT. A literature search was performed on PubMed to identify original articles that evaluated the effects of an exercise program to alleviate treatment-related side effects in cancer patients undergoing RT with or without other cancer treatments. Benefits related to exercise training have been shown in breast, prostate, rectal, lung, head and neck cancer patients undergoing RT. Therefore, exercise should be considered as a concurrent treatment alongside RT to alleviate treatment-related side effects and facilitate effective recovery. Due to the onset and progress of treatment-related side effects throughout RT, a regular clinical evaluation seems strongly advisable in order to continuously adapt the exercise programme depending on symptoms and side effects. An exercise professional is needed to personalize exercise training based on the medical condition and tailor it throughout the intervention according to progress and the patient's medical status. Future studies are needed to confirm the potential benefits of exercises observed on treatment-related side effects. Furthermore, because of the narrative design of this study, a systematic review is required to evaluate the strength of the evidence reported

Tumor response to EGFR/BRAF/MEK co-inhibition in a patient with EGFR mutated lung adenocarcinoma developing a BRAF mutation as an acquired resistance mechanism.

EGFR-mutant adenocarcinomas represent 12% of unselected lung adenocarcinomas and 44% of never smoker adenocarcinomas in the Caucasian population. Activating mutations like exon19 deletion or exon21 Leu858Arg point mutations are predictive of tumor response to EGFR tyrosine kinase inhibitors. Unfortunately, acquired resistance inevitably occurs by the development of novel EGFR mutations, mutations in other genes, gene amplification, gene fusion or tumor transformation. The management of tumors presenting multiple targetable mutations is unclear. We present the case of a patient developing a BRAF mutation as acquired resistance mechanism to osimertinib, who responded favorably to the combination of dabrafenib, trametinib and osimertinib

Telerehabilitation physical exercise for patients with lung cancer through the course of their disease: A systematic review.

BACKGROUND AND OBJECTIVE: Evidence is shown for the benefits of physical activity, for patients with lung cancer, at different times through the course of the disease. Telerehabilitation can overcome some of barriers often met by patients to practice physical activity. The objective of this systematic review is to assess feasibility and safety of telerehabilitation for patients with lung cancer, its effects on physical capacity, quality of life, symptoms severity, depression and anxiety, survival, lung function, post-operative outcomes, dyspnoea and body composition. Secondary aim was to distinguish the telerehabilitation efficacy between the different phases of the disease. DATA SOURCE AND SELECTION CRITERIA: Pubmed, PEDro, Scopus, ScienceDirect, randomized controlled trials and non-randomized controlled trials, written in French or English, of telerehabilitation among patients with lung cancer. RESULTS: Eight studies were included. Telerehabilitation is safe but was characterized by a low recruitment and attendance rate (<70%). It enhances quality of life, muscle mass, depression and anxiety but it does not improve physical capacity (except in preoperative period), symptoms severity, survival, lung function or dyspnoea. After surgery, it ameliorates quality of life, depression and anxiety. During systemic treatments of lung cancer, it improves quality of life, symptoms severity and muscle mass. CONCLUSION: Telerehabilitation could be proposed in patients with lung cancer as a complementary intervention of hospital-based programme to increase physical activity volume, compliance and self-efficacy. In case the classic programmes are not possible, it could also be an alternative approach for patients unable to participate to a hospital or community-based training programme

AB1579 Ultrasound joint assessments increase detection of polyarticular joint involvement in checkpoint inhibitors induced arthritis

BACKGROUND: CheckPoint Inhibitors (CPI) Induced arthritis (IA) is an immune related adverse event (irAEs) occurring in 0.5 to 2% of CPI-treated patients between 3 weeks up to 24 months after initiation of therapy. IA is usually described as a seronegative oligoarticular inflammatory joint disease but IA has been for long underdiagnosed and inappropriately evaluated. OBJECTIVES: To evaluate the added value of a systematic joint ultrasound assessment in these patients by the rheumatologist. […

Multiplex Immunofluorescence Combined with Spatial Image Analysis for the Clinical and Biological Assessment of the Tumor Microenvironment

The tumor microenvironment (TME) is composed of a plethora of different cell types, such as cytotoxic immune cells and immunomodulatory cells. Depending on its composition and the interactions between cancer cells and peri-tumoral cells, the TME may affect cancer progression. The characterization of tumors and their complex microenvironment could improve the understanding of cancer diseases and may help scientists and clinicians to discover new biomarkers. We recently developed several multiplex immunofluorescence (mIF) panels based on tyramide signal amplification (TSA) for the characterization of the TME in colorectal cancer, head and neck squamous cell carcinoma, melanoma, and lung cancer. Once the staining and scanning of the corresponding panels are completed, the samples are analyzed on an image analysis software. The spatial position and the staining of each cell are then exported from this quantification software into R. We developed R scripts that allow us not only to analyze the density of each cell type in several tumor compartments (e.g. the center of the tumor, the margin of the tumor, and the stroma) but also to perform distance-based analyses between different cell types. This particular workflow adds a spatial dimension to the classical density analysis already routinely performed for several markers. mIF analysis could allow scientists to have a better understanding of the complex interaction between cancer cells and the TME and to discover new predictive biomarkers of response to treatments, such as immune checkpoint inhibitors, and targeted therapies