W222 - Pro-inflammatory and Exhausted T Cell Signatures Characterize Severe Male Infertility

Luca Boeri – Department of Urology, Foundation IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, University of Milan, Milan, Lombardia, Italy; Edoardo Pozzi – Division of Experimental Oncology/Unit of Urology; URI – IRCCS Ospedale San Raffaele, Milan, Lombardia, Italy; Federico Belladelli – Division of Experimental Oncology/Unit of Urology; URI – IRCCS Ospedale San Raffaele, Milan, Lombardia, Italy; Luca Valsecchi – University Vita-Salute San Raffaele, Milan, Lombardia, Italy; Francesco Montorsi – Division of Experimental Oncology/Unit of Urology; URI – IRCCS Ospedale San Raffaele, Milan, Lombardia, Italy; Massimo Alfano – Division of Experimental Oncology/Unit of Urology; URI – IRCCS Ospedale San Raffaele, Milan, Lombardia, Italy; Andrea Salonia – Division of Experimental Oncology/Unit of Urology; URI – IRCCS Ospedale San Raffaele, Milan, Lombardia, Italy; Silvia Gregori – San Raffaele Telethon Institute for Gene Therapy – IRCCS Ospedale San Raffaele, Milan, Lombardia, Italy

Abstract Text: Severe male infertility has been associated with low health status and earlier onset of age-associated comorbidities compared to fertile men. Besides, men with idiopathic non-obstructive azoospermia (iNOA) display a proinflammatory signature in the testis. In the hypothesis that a deregulation of the immune system could associate to infertility and impact the healthiness of severe infertile men, for the first time, we comprehensively analyzed by multiparametric flow cytometry and scRNAseq analysis the immune status of infertile men in comparison age-matched fertile men.
Severe infertile men showed a higher frequency of granulocytes and proinflammatory dendritic cells (DC) in sperm fluid and peripheral blood compared to fertile men and an overall proinflammatory signature in both tissues. Despite the lower frequency of CD4+ and CD8+ T cells in peripheral blood of infertile men, these cells co-expressed exhaustion markers (PD-1, TIM-3, KLRG-1, Eomes, and T-Bet) at higher frequency compared to cells from fertile men. Functional studies indicated that CD8+ T cells from severe infertile men were slightly hypo-proliferating and produced lower levels of GM-CSF and IL-2 compared to T cells from fertile men.
Our results reported a previously undescribed association between severe male infertility and a systemic and local proinflammatory immune status, with circulating T cells phenotypically and functionally resembling exhausted T cell precursors. Overall, our study could explain the low health status of infertile men and will be instrumental to improve the clinical management of male infertile subjects.