No abstract

An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumourigenic 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 a coordinated activation of NF-B 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-PD1/PDL1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumours was enriched in key indicators of 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.

Cutaneous melanomas are a prime example of tumors with the potential to express a broad spectrum of neoantigens. These result from the highest mutational rate described to date, and the accumulation of a plethora of post-transcriptional and post-translational alterations. However, a significant fraction of metastatic melanoma patients are or become resistant to current immunotherapeutic agents. How lesions that should represent an inherently hot milieu for immune attack are shifted into immunologically cold or irresponsive neoplasms is not well understood. Combining cellular systems, mouse models and clinical datasets, here we identify the growth factor Midkine (MDK) as a multipronged blocker of antigen presentation. Mechanisticallyt, we found MDK to repress all main aspects of the maturation, activation and function of dendritic cells, particularly of conventional type I (cCD1).These roles of MDK were found to involve primary tumors and lymph nodes, and were traced back to suppressive effects on myeloid precursor cells in the bone marrow. Moreover, MDK shifted DCs to a distinct tolerogenic state that prevented and bypassed CD8+ T cell activation. Together, these data provide insight into how melanomas overcome immune surveillance, supporting MDK as a target for therapeutic intervention.