W152 - Immune Alterations Typically Associated with Inflammaging Characterize Severe Infertile Men

Giorgia Giacomini – San Raffaele Telethon Institute for Gene Therapy (SR-TIGET); Luca Boeri – IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinic; Massimiliano Raffo – University Vita-Salute San Raffaele, Milan; Simone Cilio – University of Naples “Federico II”, Naples; Edoardo Pozzi – IRCCS Ospedale San Raffaele, Milan; Federico Belladelli – IRCCS Ospedale San Raffaele, Milan; Fausto Negri – IRCCS Ospedale San Raffaele, Milan; Anna Maria Ferrara – IRCCS Ospedale San Raffaele, Milan; Alessia d'Arma – IRCCS Ospedale San Raffaele, Milan; Francesca Santoni de Sio – San Raffaele Telethon Institute for Gene Therapy (SR-TIGET); Luca Pagliardini – IRCCS Ospedale San Raffaele, Milan; Enrico Papaleo – IRCCS Ospedale San Raffaele, Milan; Eugenio Ventimiglia – IRCCS Ospedale San Raffaele, Milan; Massimo Alfano – IRCCS Ospedale San Raffaele, Milan; Francesco Montorsi – IRCCS Ospedale San Raffaele, Milan; Andrea Salonia – IRCCS Ospedale San Raffaele, Milan; Silvia Gregori – San Raffaele Telethon Institute for Gene Therapy (SR-TIGET)

Abstract Text: Infertile men are at high risk of premature development of non-malignant and malignant non-communicable diseases (NCDs). The association among male health status, immune asset, and infertility is still undefined. By multiparameter phenotyping and scRNAseq we delineated the immune status of relatively young (median age of 37 years) severe infertile men with either oligo-astheno-teratozoospermia (OAT) or idiopathic non-obstructive azoospermia (iNOA). Overall, infertile men are characterized by a pro-inflammatory environment in the semen and the peripheral blood defined by enrichment in neutrophils, inflammatory dendritic cells and soluble mediators, and reduction of lymphoid cells. These features are typically observed in healthy elderly men and are comprehensively defined as inflammaging, an unresolved systemic inflammation observed in aged individuals and associated with the emergence of several NCDs. Mechanisms leading to inflammaging include cellular senescence, oxidative stress, and immune cell dysregulation. Notably, scRNAseq of T cells from peripheral blood of OAT and iNOA men revealed an overall high rate of differentiated/effector cells with T cells from OAT patients displaying a signature of exhaustion whereas T cells from iNOA patients having a signature of senescence. Both features further sustain the hypothesis of an early aged immune system in infertile men and revealed a different inflammatory nature between OAT and iNOA men.
This study provides first demonstration that, despite being overall young and clinically healthy individuals, infertile men present an immune profile typically associated with inflammaging, and that OAT and iNOA constitute two different diseases with the potential to develop different secondary infertility-associated NCDs.