Since the recruitment and polarization of TAMs are regulated by CSF-1R/CSF-1, the expression levels of these factors may be indicative of TAM physiology and correlated with antitumoral immunity and response to therapy. This study aimed to investigate the influence of CSF-1R/CSF-1 activation levels on tumor response in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line immune checkpoint inhibitor (ICI) therapy. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC treated with ICIs as first-line therapy. Plasma levels of CSF-1 were assessed by ELISA. Peripheral blood mononuclear cells were used both for immunomodulatory assays and to produce macrophages through CSF-1 treatment. To assess the mechanism of CSF-1-mediated suppression of immunotherapy, Isolated PBMC, activated with phytohemagglutinin (PHA) with or without pembrolizumab (20 nM), were cultured alone, or in the presence of macrophages or on an established NSCLC monolayer. INFγ levels and CD8+ proliferation/activation were assessed through ELISA assay and flow cytometry respectively. Plasma levels of CSF-1 were found to be higher in patients resistant to ICI therapy (8898 vs. 14031 pg/mL, p < 0.001). Higher levels of CSF-1 were associated with poor therapy response (RR = 7,944; p = 0.013), disease progression (RR = 8.556; p < 0.001), and shorter survivals (PFS, 50 days vs. 305 days; p < 0.001; OS, 248 days vs. 1369 days, p < 0.01). In vitro, recombinant CSF-1 inhibited CD8+ activation and interferon gamma (INFγ) production that was induced by PHA and Pembrolizumab. The use of Pexidartinib (PLX-3397), a CSF-1R inhibitor, reversed the effects of CSF-1 by restoring lymphocyte activation. However, these effects were dependent on the presence of monocytes/macrophages, suggesting that the immune suppression mediated by CSF-1 was an indirect effect resulting from the stimulation of monocytes that promote their differentiation into macrophages. Our study suggests that plasma levels of CSF-1 could serve as a useful predictive biomarker for resistance to ICIs, while targeting the CSF-1/CSF-1R signaling pathway could potentially overcome resistance to ICIs in patients with NSCLC.

The identification of biomarkers related to treatment in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) represents a significant challenge. The aim of this study was to determine the predictive value of macrophage-related markers assessed in plasma and tissue samples of patients with NSCLC undergoing ICI treatment. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC who received first -line therapy with ICI (either as monotherapy or in combination with chemotherapy) or chemotherapy alone (CT). Samples were collected from the patients at baseline and during follow-up. Plasma levels of CSF-1 and IL-34 were measured using ELISA, while expression levels of the macrophage receptors CD163 and CSF-1-R were evaluated using immunohistochemistry on lung biopsies. At baseline, the median plasma CSF-1 expression was higher in patients who did not respond to immunotherapy compared to those who responded (8898 pg/mL vs. 14031 pg/mL, p = 0.0005). Importantly, high CSF-1 levels at the initial assessment were associated with disease progression regardless of the treatment received. Furthermore, high CSF-1 levels were associated with shorter progression-free survival (PFS) and overall survival (OS) in patients receiving ICI therapy, but not in those treated with chemotherapy. There was no correlation between IL-34, CSF1R, CD163 and therapeutic response. We observed in vitro that the activation of lymphocytes mediated by pembrolizumab was hindered by the treatment of PBMC with recombinant CSF-1, suggesting that CSF-1 creates a systemic immunosuppressive state that interferes with ICI treatment. In conclusion, baseline CSF-1 levels represent a potential predictive marker to ICI treatment in NSCLC.

Immune checkpoint inhibitors (ICIs) are now widely used in monotherapy or in combination with chemotherapy in advanced non-small cell lung cancer (NSCLC), and in combination with chemotherapy in advanced small-cell lung cancer (SCLC). However, few data are currently available concerning the acquired resistance mechanisms to ICIs in lung cancer. There is therefore a need for systematic prospective collection of tumor samples for histological and molecular analyses at the time of progression. REBIMMUNE trial is a prospective, bicentric trial (2 academic centers), that includes consecutive patients with advanced NSCLC or SCLC treated with ICIs (alone or in combination with chemotherapy) experiencing tumor progression while on ICIs. After signature of a consent form, the patients have a new tumor biopsy on a progressive tumor site. On these samples, we will perform various immunohistochemistry tests, including PTEN, Beta-2-microglobuline (B2M), Beta-catenin (Wnt pathway activation), CD8 and PD-L1 expressions. We will also perform targeted molecular screening on PTEN, JAK and B2M genes along with NGS panels. We will compare these results with those performed on corresponding diagnosis samples, and correlate them with clinical outcomes (response rate, progression-free survival, overall survival). We plan to include 100 patients in 2 years. NCT04300062. Assistance Publique - Hopitaux de Paris (APHP). Has not received any funding.

L’hypertension pulmonaire (HTP) précapillaire est une complication de la drépanocytose homozygote SS, dont la prévalence est estimée à 2 %. Malgré son impact sur le pronostic fonctionnel et vital des patients, très peu de données sur sa prise en charge sont actuellement disponibles. L’effet des échanges érythocytaires (EE) répétés sur cette complication sévère n’a jamais été étudié. Étude rétrospective monocentrique dont l’objectif principal était d’étudier l’effet des EE sur les résistances vasculaires pulmonaires (RVP). L’évolution du test de marche de six minutes (TM6), de la classe fonctionnelle NYHA (CF-NYHA) et des paramètres biologiques d’hémolyse après EE a également été étudiée. Vingt-trois sujets drépanocytaires homozygotes SS avec HTP précapillaire ont été identifiés entre 2000 et 2017 dans le centre de référence français de l’HTP. Treize d’entre eux ont bénéficié d’EE chroniques, en première intention dans 8 cas et après échec d’un traitement médical dans 5 cas. Il s’agissait d’érythraphérèse dans 10 cas et d’échanges manuels dans 3 cas. Après un nombre médian de 4 échanges transfusionnels, une amélioration hémodynamique significative a été observée avec une baisse des valeurs médianes des RVP de 3,7 à 2,8 UW (p = 0,006) et une baisse de la pression artérielle pulmonaire moyenne de 40 à 35 mmHg (p = 0,008). Cette amélioration s’accompagnait d’une baisse significative du taux sérique de lactate déshydrogénase (789 UI/L après EE vs 1062 UI/L avant, p = 0,024). Soixante-dix-sept des patients étaient en CF I-II de la NYHA sous EE avec une amélioration non significative de la distance médiane parcourue au TM6 de 223 à 398 mètres (p = 0,06). En comparaison au groupe témoin non traité par EE, l’amélioration de la CF-NYHA et de la distance parcourue au TM6 était significativement plus importante. Aucun patient n’est décédé dans les deux ans suivant le diagnostic d’HTP précapillaire dans le groupe traité par EE. Dans le groupe témoin, 3 patients sont décédés dans les 6 mois suivant le diagnostic. Les EE chroniques semblent permettre d’obtenir une baisse significative des RVP chez les patients drépanocytaires SS souffrant d’HTP précapillaire. Ces données doivent être confirmées par une étude prospective.

Essentials The reproducibility of Clinical Events Committee (CEC) adjudications is almost unexplored. A random selection of events from a venous thromboembolism trial was blindly re‐adjudicated. ‘Unexplained sudden deaths’ (possible fatal embolism) explained most discordant adjudications. A precise definition for CEC adjudication of this type of events is needed and proposed.