Sub-aortic obstruction of left ventricular outflow tract secondary to benfluorex-induced endocardial fibrosis

Patients exposed to benfluorex have an increased risk of restrictive organic valvular heart disease. Aortic and mitral regurgitations caused by fibrotic valve disease are the most common features observed in exposure to fenfluramine derivatives in general and benfluorex in particular. We report here, for the first time to our knowledge, a well-documented case in which obstructive sub-aortic endocardium fibrosis within the left ventricular outflow tract is related with exposure to a drug that modifies the metabolism of serotonin. It now remains to be established whether extensive fibrosis of the myocardium in addition to well-documented valvular fibrosis may develop in patients exposed to amphetamine-derived drugs affecting the serotonin system

Integrin-α(V)-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade

International audienceTGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin α(V) subunit. The activation of latent TGF-β by cancer-cell-expressed α(V) re-shapes the tumour microenvironment, and this could affect patient responses to PD-1-targeting therapy. Here we show, using multiplex immunofluorescence staining in cohorts of anti-PD-1 and anti-PD-L1-treated lung cancer patients, that decreased expression of cancer cell α(V) is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8(+)CD103(+) tumour-infiltrating lymphocytes. Mechanistically, tumour α(V) regulates CD8 T cell recruitment, induces CD103 expression on activated CD8(+) T cells and promotes their differentiation to granzyme B-producing CD103(+)CD69(+) resident memory T cells via autocrine TGF-β signalling. Thus, our work provides the underlying principle of targeting cancer cell α(V) for more efficient PD-1 checkpoint blockade therapy

CD103+CD8+ TRM Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17

International audienceAccumulation of CD103+CD8+ resident memory T (TRM) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of TRM to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103+CD8+ lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103+CD8+ cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103+CD8+ cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103+CD8+ tumor TRM, but not CD103-CD8+ tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103+CD8+ TRM are associated with better outcomes in anti-PD-(L)1-treated patients