Sex-related changes in LDH-A expression differently impact on immune response in melanoma

<p><span>Marta Iozzo1, Giuseppina Comito1, Luigi Ippolito1, Giada Sandrini2, Elisa Pardella1, Erica Pranzini1,<strong> </strong>Mariaelena Capone3, Gabriele Madonna3, Paolo Antonio Ascierto3, Paola Chiarugi1, Elisa Giannoni1.</span></p> <p><span>1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy</span></p> <p><span>2 Institute of Oncology Research (IOR), Universit&agrave; della Svizzera Italiana (USI), Bellinzona, Switzerland</span></p> <p><span>3 Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131, Naples, Italy </span></p> <p>&nbsp;</p> <p>Abstract<br>Melanoma incidence and mortality are higher in male patients than female ones, likely associated to the sex dimorphism in immune responses. Pro- and anti-tumor immune immunity are altered by the metabolic changes occurring in the tumor microenvironment.<br>Here, we identified the lactate dehydrogenase A (LDH-A), the key enzyme deputed to the lactate production, as a crucial metabolic player discriminating sex-related melanoma immune responses both in in vitro and in patient-derived specimens. Specifically, LDH-A-associated higher lactate secretion in male melanoma cells leads to a significant enrichment in pro-tumoral regulatory T cells (Treg) with a decrease in the number and activity of anti-tumor CD8+ T cells. Remarkably, pharmacological and genetic impairment of LDH-A in male melanoma cells are able to phenocopy female ones in terms of Treg and CD8+ infiltration. In keeping, in vivo pharmacological targeting of LDH-A in melanoma-bearing male mice significantly impairs tumor growth and lung colonization, and this correlates with a concomitant modulation of Treg and CD8+ T cells infiltration. Taken together, our findings underline sex-related differences in the melanoma LDH-A-promoting immune reshaping and suggest LDH-A targeting as an effective strategy to abolish the sex-gap in melanoma progression.</p> <p>&nbsp;</p>