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

Marta Iozzo1, Giuseppina Comito1, Luigi Ippolito1, Giada Sandrini2, Elisa Pardella1, Erica Pranzini1, Mariaelena Capone3, Gabriele Madonna3, Paolo Antonio Ascierto3, Paola Chiarugi1, Elisa Giannoni1.

1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

2 Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), Bellinzona, Switzerland

3 Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131, Naples, Italy

AbstractMelanoma 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.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.

马尔塔·约佐(1), 朱塞皮娜·科米托(1), 路易吉·伊波利托(1), 贾达·桑德里尼(2), 埃莉萨·帕尔德拉(1), 埃丽卡·普兰齐尼(1), 玛丽亚埃莱娜·卡波内(3), 加布里埃莱·马达纳(3), 保罗·安东尼奥·阿斯谢罗托(3), 宝拉·基亚鲁吉(1), 埃莉萨·吉安诺尼(1)。

(1) 意大利佛罗伦萨大学实验与临床生物医学科学系
(2) 瑞士贝林佐纳瑞士意大利语大学肿瘤研究所（Institute of Oncology Research，IOR）
(3) 意大利那不勒斯80131区国立肿瘤研究所G.帕斯卡尔IRCCS基金会黑色素瘤、癌症免疫治疗与治疗开发部

摘要 黑色素瘤的发病率与死亡率在男性患者中均高于女性，这一现象可能与免疫反应的性别二态性（sex dimorphism）相关。肿瘤微环境（tumor microenvironment）内发生的代谢改变会调控促肿瘤与抗肿瘤免疫应答。本研究鉴定出乳酸脱氢酶A（lactate dehydrogenase A，LDH-A）——负责乳酸生成的关键酶——作为核心代谢调控因子，可在体外实验（in vitro）及患者来源标本（patient-derived specimens）中区分性别相关的黑色素瘤免疫应答。具体而言，男性黑色素瘤细胞中LDH-A介导的乳酸分泌升高，会导致促肿瘤调节性T细胞（regulatory T cells，Treg）显著富集，同时抗肿瘤CD8+ T细胞（CD8+ T cells）的数量与活性均显著降低。值得注意的是，对男性黑色素瘤细胞中的LDH-A进行药理学与遗传学抑制，能够在调节性T细胞与CD8+ T细胞浸润层面模拟雌性黑色素瘤细胞的表型。与此一致，在携带黑色素瘤的雄性小鼠体内开展LDH-A靶向药理学治疗，可显著抑制肿瘤生长与肺部定植，且该效应与调节性T细胞和CD8+ T细胞浸润的协同调控密切相关。综上，本研究结果揭示了黑色素瘤中LDH-A介导的免疫重塑存在性别差异，并提示靶向LDH-A可作为消除黑色素瘤进展性别差异的有效策略。