MET Oncogene Targeting for Cancer Immunotherapy

Abstract

The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is usurped by cancer cells to induce and sustain the malignant phenotype. MET stands out as one of the most important oncogenes activated in cancer and its inhibition has been explored since the initial era of cancer-targeted therapy. Different approaches have been developed to hamper MET signaling and/or reduce MET (over)expression as a hallmark of transformation. Considering the great interest gained by cancer immunotherapy, this review evaluates the opportunity of targeting MET within therapeutic approaches based on the exploitation of immune functions, either in those cases where MET impairment is crucial to induce an effective response (i.e., when MET is the driver of the malignancy), or when blocking MET represents a way for potentiating the treatment (i.e., when MET is an adjuvant of tumor fitness).

Keywords: MET antibody; MET oncogene; MET tyrosine kinase inhibitors; cellular immunotherapy; immunotherapy; targeted therapy.

Figure 1

Schematic representation of the MET receptor (left) and its activation upon ligand interaction, eliciting MET phosphorylation and triggering intracellular signaling responses (right). SEMA: semaphorin domain; blades 1–3 (in red) constitute the α-chain; blades 4–7 (in blue) belong to the β-chain; PSI: plexin–semaphorin–integrin homology domain; IPT 1–4: four immunoglobulin–plexin–transcription factor domains; JM: juxtamembrane domain; TKD: tyrosine kinase domain; DS: docking site. Relevant tyrosine residues (in yellow if phosphorylated) are highlighted.

Figure 2

Schematic representation of the modulation exerted by the HGF/MET signaling on the immunosuppressive status of the tumor and its microenvironment. Red arrows represent an upregulation of immunosuppression induced upon HGF/MET axis activation; blue arrows indicate a reduction in immunostimulatory events caused by the axis. In the inset, a magnification shows immune cell populations infiltrating the tumor microenvironment. CAFs: Cancer-Associated Fibroblasts; DCs: Dendritic cells; MDSCs: Myeloid-Derived Suppressor Cells; TAN: Tumor-Associated Neutrophil; APCs: Antigen-Presenting Cells.

Figure 3

MET-CAR-T cellular immunotherapy designs and applications in different types of cancer. (A). MET-CAR-T cells are generated by genetic engineering of T lymphocytes with a CAR sequence. MET-CAR-T cells, sparing normal tissue while hitting MET-expressing tumor cells, have been tested in the indicated cancer models, either by locoregional delivery (left) or by systemic delivery (right). (B). MET-CAR-T cells have been applied in combination with targeting molecules (Axitinib or Nimotuzumab) in renal or nasopharyngeal carcinoma models, respectively. (C). Bispecific MET-CAR-T cells binding concomitantly with the MET receptor and an immune checkpoint molecule, PD-1 (left) or PD-L1 (right), have been evaluated against gastric or hepatocellular carcinoma, respectively. (D). T cells co-expressing a MET-CAR and a Chimeric Switch Receptor (CSR) have been investigated to potentiate the immune cell-mediated killing of gastric cancer cells. The therapeutic strategies evaluated in clinical trials are indicated in the figure.