西班牙国家癌症研究中心(CNIO) Mara S. Soengas和David Olmeda课题组合作取得一项新成果。他们发现Midkine重塑黑色素瘤微环境导致免疫耐受和免疫抵抗状态的产生。2020年10月19日的《自然-医学》发表了这项成果。

研究人员发现在炎性但免疫逃逸的微环境中，黑色素瘤分泌的驱动因子Midkine（MDK）预示了不良患者预后和对免疫检查点阻滞的抵抗。从机制上讲，MDK调控黑素瘤细胞的转录组，协同激活调控核因子-κB以及下调干扰素相关途径。MDK调控分泌蛋白组诱导巨噬细胞产生促进CD8⁺ T细胞功能障碍耐受的表型。相反，靶向MDK导致黑色素瘤细胞对抗PD-1 /抗PD-L1治疗敏感。

这些发现强调了翻译相关性，MDK缺失肿瘤的表达谱丰富了独立患者队列中对免疫检查点阻滞疗法反应的关键指标。总得来说，这些数据表明MDK充当自分泌和旁分泌信号的内部调节因子，可在侵袭性黑素瘤中维持免疫抑制。

据了解，在诸如黑色素瘤等侵袭性癌症中，一个悬而未决的问题是，恶性细胞如何重塑免疫系统使其发挥促癌功能。

附：英文原文

Title: Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state

Author: Daniela Cerezo-Wallis, Marta Contreras-Alcalde, Kevin Troul, Xavier Catena, Cynthia Mucientes, Tonantzin G. Calvo, Estela Can, Cristina Tejedo, Paula C. Pennacchi, Sabrina Hogan, Peter Klblinger, Hctor Tejero, Andrew X. Chen, Nuria Ibarz, Osvaldo Graa-Castro, Lola Martinez, Javier Muoz, Pablo Ortiz-Romero, Jos L. Rodriguez-Peralto, Gonzalo Gmez-Lpez, Ftima Al-Shahrour, Ral Rabadn, Mitchell P. Levesque, David Olmeda, Mara S. Soengas

Issue&Volume: 2020-10-19

Abstract: An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas. Tumor-secreted midkine modulates immune tolerance in the melanoma tumor microenvironment and determines resistance to immune checkpoint blockade.

DOI: 10.1038/s41591-020-1073-3

Source: https://www.nature.com/articles/s41591-020-1073-3