Novel Therapeutics and the Path Toward Effective Immunotherapy in Malignant Peripheral Nerve Sheath Tumors

Abstract

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently "cold" tumor microenvironment into a "hot" immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy.

Keywords: MPNST; immunotherapy; targeted therapy.

Figure 1

Hallmark alterations during the malignant transformation of PNFs into ANNUBPs and MPNSTs. Plexiform neurofibromas (PNFs) are initiated by the loss of NF1. Atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBPs) are intermediate lesions characterized by an additional loss of CDKN2A. They also overexpress RABL6A and PD-L1 proteins. Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are the fully transformed lesion, with additional losses of the TP53, SUZ12, and EED genes. MPNSTs also express more RABL6A, PD-L1, and MET proteins. These alterations cooperate to enhance Ras signaling and suppress RB1 activity as PNFs transform into MPNSTs. Loss, (−). Overexpression, (+); magnitude indicated by the number of (+).

Figure 2

Select genetic and molecular drivers of MPNST pathogenesis. The loss of neurofibromin activates Ras, which signals through PI3K/AKT/mTOR and Raf/MEK/ERK pathways. The MET receptor (as well as other receptor tyrosine kinases like EGFR, PDGFR, and TYK2) signals through mTOR and ERK pathways through the activation of the SHP2 phosphatase. The loss of p16 activates CDK4/6, thereby inhibiting RB1. The inhibition of RB1 allows E2F to transcribe genes critical for S-phase entry, like CCNE1. The loss of ARF activates MDM2, destabilizing p53. p53 inactivation can also occur independently of ARF loss. RABL6A alters many pathways in MPNSTs, including the activation of MEK, Myc, CDK4/6, and MDM2 through independent mechanisms. Major tumor suppressors lost by genetic alterations in MPNSTs are designated as red X’s. Select listing of available pharmacologic inhibitors targeting MPNST drivers is shown in bolded blue text.

Figure 3

Classes of immunotherapy being tested in MPNSTs and their mechanisms of action. (a) Oncolytic viruses work by infecting tumor cells and lysing the tumor (depicted in red) upon replication. The spilled cytosolic contents can be taken up by antigen-presenting cells (APCs), which can then present antigens to T cells. (b) Myeloid cells secrete factors to promote tumor growth (green spheres) and directly inhibit T-cell cytotoxicity (blue spheres). CSFR1 inhibitors have been shown to deplete macrophages, and trabectedin has been reported to suppress both macrophages (Macs) and myeloid-derived suppressor cells (MDSCs). (c) Immune checkpoint blockades function by sustaining the T-cell response. PD-L1 (and other molecules) on the tumor cell (top, pink) bind receptors like PD-1 on T cells (bottom, green) to suppress CD8+ T-cell activity. Antibodies targeting either checkpoint protein can disrupt this interaction and sustain the T-cell response.