Abstract
Expression of MDK, encoding the growth factor midkine, led to immunotherapy resistance in melanoma.
Major Finding: Expression of MDK, encoding the growth factor midkine, led to immunotherapy resistance in melanoma.
Concept: MDK or Mdk expression in vivo caused recruitment of immunosuppressive myeloid cells to tumors.
Impact: Immune checkpoint blockade efficacy may be hindered by MDK, so MDK targeting may be of interest.
Although the heparin-binding growth factor midkine (MDK) has been found to prime the premetastatic niche in melanoma, its potential role modulating the tumor immune microenvironment in this malignancy has not been well characterized. To investigate this, Cerezo-Wallis and colleagues started by generating isogenic cell lines that either expressed or lacked MDK. They then performed RNA sequencing to determine the transcriptomic effects of MDK expression in melanoma cells. Examination of data from The Cancer Genome Atlas (TCGA) revealed that melanomas with transcriptional profiles similar to those of the MDK-expressing cells were associated with poorer patient prognoses. In vivo, MDK or Mdk expression in human or murine melanoma tumors, respectively, promoted the recruitment of immunosuppressive myeloid cells to the tumors. Transcriptomic and proteomic analyses were then performed to define MDK-controlled genes in melanoma cells and in the extracellular microenvironment. These studies revealed several connected gene networks acting downstream of MDK, with NF-κB appearing to act as a key regulator. Importantly, high Mdk expression in mouse melanomas led to resistance to immune checkpoint blockade with anti–PD-1 or anti–PD-L1, whereas Mdk knockdown had the opposite effect, sensitizing tumors to the immunotherapies. Macrophages exposed to MDK-expressing tumors acted to suppress CD8+ T-cell function, reducing the T cells' cytotoxicity toward tumor cells, highlighting the possibly immunosuppressive role of MDK in the tumor microenvironment. Finally, in patients with melanoma, overlap of the tumor gene-expression profile with that of MDK-deficient tumors observed in the prior analyses corresponded with an increased chance of response to immune checkpoint blockade. MDK-associated immunomodulatory profiles were also found in TCGA cohorts of patients with other cancer types (glioblastoma, lung adenocarcinoma, and renal adenocarcinoma). Together, these findings identify MDK as a factor that may contribute to immunosuppression in the tumor microenvironment at a detriment to the efficacy of immunotherapies.
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