1. Academic Validation
  2. Sex-related changes in lactate dehydrogenase A expression differently impact the immune response in melanoma

Sex-related changes in lactate dehydrogenase A expression differently impact the immune response in melanoma

  • FEBS J. 2025 Jan 31. doi: 10.1111/febs.17423.
Marta Iozzo 1 Giuseppina Comito 1 Luigi Ippolito 1 Giada Sandrini 2 Elisa Pardella 1 Erica Pranzini 1 Mariaelena Capone 3 Gabriele Madonna 3 Paolo Antonio Ascierto 3 Paola Chiarugi 1 Elisa Giannoni 1
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
  • 2 Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), Bellinzona, Switzerland.
  • 3 Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
Abstract

Melanoma is more aggressive in male patients than female ones and this is associated with sexual dimorphism in immune responses. Taking into consideration the impact tumour metabolic alterations in affecting the immune landscape, we aimed to investigate the effect of the sex-dependent metabolic profile of melanoma in re-shaping immune composition. Melanoma is characterised by Warburg metabolism, and secreted lactate has emerged as a key driver in the establishment of an immunosuppressive environment. Here, we identified Lactate Dehydrogenase A (LDH-A) as a crucial player in modulating sex-related differences in melanoma immune responses, both in vitro and in patient-derived specimens. LDH-A is associated with higher lactate secretion in male melanoma cells, which leads to a significant enrichment in pro-tumoural regulatory T cells (Treg) with a concurrent decrease in the number and activity of anti-tumour CD8+ T cells. Remarkably, pharmacological and genetic impairment of LDH-A in male melanoma cells normalises Treg and CD8+ infiltration. In keeping with this, in vivo pharmacological targeting of LDH-A in melanoma-bearing male mice impairs tumour growth and lung colonisation, with a concomitant modulation of Treg and CD8+ T cells infiltration. Taken together, our findings highlight the sex-related differences promoted by LDH-A in immune reshaping in melanoma, and suggest that therapeutic targeting of LDH-A could be leveraged as an effective strategy to abolish the sex-gap in melanoma progression.

Keywords

CD8+; Treg; lactate; melanoma; sex.

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