Natural killer cells and neuroblastoma: tumor recognition, escape mechanisms, and possible novel immunotherapeutic approaches

Abstract

Neuroblastoma (NB) is the most common extra-cranial solid tumor of childhood and arises from developing sympathetic nervous system. Most primary tumors localize in the abdomen, the adrenal gland, or lumbar sympathetic ganglia. Amplification in tumor cells of MYCN, the major oncogenic driver, patients' age over 18 months, and the presence at diagnosis of a metastatic disease (stage IV, M) identify NB at high risk of treatment failure. Conventional therapies did not significantly improve the overall survival of these patients. Moreover, the limited landscape of somatic mutations detected in NB is hampering the development of novel pharmacological approaches. Major efforts aim to identify novel NB-associated surface molecules that activate immune responses and/or direct drugs to tumor cells and tumor-associated vessels. PVR (Poliovirus Receptor) and B7-H3 are promising targets, since they are expressed by most high-risk NB, are upregulated in tumor vasculature and are essential for tumor survival/invasiveness. PVR is a ligand of DNAM-1 activating receptor that triggers the cytolytic activity of natural killer (NK) cells against NB. In animal models, targeting of PVR with an attenuated oncolytic poliovirus induced tumor regression and elimination. Also B7-H3 was successfully targeted in preclinical studies and is now being tested in phase I/II clinical trials. B7-H3 down-regulates NK cytotoxicity, providing NB with a mechanism of escape from immune response. The immunosuppressive potential of NB can be enhanced by the release of soluble factors that impair NK cell function and/or recruitment. Among these, TGF-β1 modulates the cytotoxicity receptors and the chemokine receptor repertoire of NK cells. Here, we summarize the current knowledge on the main cell surface molecules and soluble mediators that modulate the function of NK cells in NB, considering the pros and cons that must be taken into account in the design of novel NK cell-based immunotherapeutic approaches.

Keywords: B7-H3; PVR; TGF-beta; chemokine receptors; immunotherapeutic approaches; natural killer cells; neuroblastoma; tumor escape mechanisms.

Figure 1

Inhibitory and activating interactions between human NK cells and neuroblasts. NB express ligands that are recognized by NK receptors with activating or inhibitory function. While DNAM-1/PVR interactions play a pivotal role in triggering NK cell-mediated killing, B7-H3 dampens NK cell function. NB usually lack or express low, non-protective levels of HLA class I molecules. However, therapeutic approaches such as the in vivo administration of anti-GD2 Abs could induce not only ADCC of NB but also the release of INF-γ, which upregulates the expression of the ligands for inhibitory KIR.

Figure 2

NB-mediated mechanisms of escape from the NK-mediated immunosurveillance. (A) Downregulation of PVR, ligand of DNAM-1 activating receptor, renders NB cells poorly susceptible to NK-mediated killing. (B) NB can release soluble MICA, exosome-associated B7-H3, immunomodulatory factors such as MIF and TGF-β1. TGF-β1 might be also released by tumor-associated macrophages (TAM) that display M2-like functional properties.

Figure 3

Possible immunotherapeutic approaches that target B7-H3 and trigger NK cell function. (A) Anti-B7-H3 antibodies induce ADCC of NK cells against NB. (B) Bi-specific antibodies that react with B7-H3 on NB and trigger activating receptors on NK cells. (C) NK cells engineered with B7-H3-specific CAR that transduce activating signals via CD3 chain.