Potential therapies for immune-related adverse events associated with immune checkpoint inhibition: from monoclonal antibodies to kinase inhibition.

The therapeutic benefits of immune checkpoint inhibitors (ICIs), which enable antitumor immune responses, can be tempered by unwanted immune-related adverse events (irAEs). Treatment recommendations stratified by irAE phenotype and immunohistopathological findings have only recently been proposed and are often based on those used in primary autoimmune diseases, including targeting of specific proinflammatory cytokines with monoclonal antibodies. Increasing evidence supports the use of such antibody-based strategies as effective steroid-sparing treatments, although the therapies themselves may be associated with additional drug toxicities and reduced ICI efficacy. Kinases are key contributors to the adaptive and innate responses that drive primary autoimmune diseases and irAEs. The janus kinase/signal transducer and activator of transcription, Bruton's tyrosine kinase, and mitogen-activated protein kinase-interacting serine/threonine protein kinases 1 and 2 pathways are also critical to tumor progression and have important roles in cells of the tumor microenvironment. Herein, we review the histopathological, biological, and clinical evidence to support specific monoclonal antibodies and kinase inhibition as management strategies for irAEs.

MNK1 signaling induces an ANGPTL4-mediated gene signature to drive melanoma progression.

The BRAFV600E mutation occurs in more than 50% of cutaneous melanomas, and results in the constitutive activation of the mitogen-activated protein kinases (MAPK) pathway. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) are downstream effectors of the activated MAPK pathway, and important molecular targets in invasive and metastatic cancer. Despite the well-known role of MNK1 in regulating mRNA translation, little is known concerning the impact of its aberrant activation on gene transcription. Here, we show that changes in the activity, or abundance, of MNK1 result in changes in the expression of pro-oncogenic and pro-invasive genes. Among the MNK1-upregulated genes, we identify Angiopoietin-like 4 (ANGPTL4), which in turn promotes an invasive phenotype via its ability to induce the expression of matrix metalloproteinases (MMPs). Using a pharmacologic inhibitor of MNK1/2, SEL201, we demonstrate that BRAFV600E-mutated cutaneous melanoma cells are reliant on MNK1/2 for invasion and lung metastasis.

Expression of SMRTbeta promotes ligand-induced activation of mutated and wild-type retinoid receptors.

Nuclear receptors are ligand-modulated transcription factors regulated by interactions with corepressors and coactivators, whose functions are not fully understood. Acute promyelocytic leukemia (APL) is characterized by a translocation, t(15;17), that produces a PML/RARalpha fusion oncoprotein, whose abnormal transcriptional function is successfully targeted by pharmacologic levels of all-trans-retinoic acid (ATRA). Mutations in the ligand-binding domain of PML/RARalpha that confer resistance to ATRA have been studied by expression in nonhematopoietic cells, such as Cos-1. Here, we show that ATRA binding and transcriptional activation by the same PML/RARalpha mutant differ markedly between nonhematopoietic and leukemic cell lines. Differential expression of the corepressor isoform silencing mediator for retinoid and thyroid receptors beta (SMRTbeta) correlates with increased ligand binding and transcription by the mutant PML/RARalpha. Transient and stable overexpression of SMRTbeta in hematopoietic cells that only express SMRTalpha increased ATRA binding, ligand-induced transcription, and ATRA-induced cell differentiation. This effect may not be limited to abnormal nuclear receptors, because overexpression of SMRTbeta increased ATRA-induced binding and transcriptional activation of wild-type receptors PML/RARalpha and RARalpha. Our results suggest a novel role for the SMRTbeta isoform whereby its cell-specific expression may influence the binding and transcriptional capacities of nuclear receptors, thus providing new evidence of distinct functions of corepressor isoforms and adding complexity to transcriptional regulation.