Cancer stem cells-driven tumor growth and immune escape: the Janus face of neurotrophins

Neurotrophins in CSCs-driven tumor growth

Neurotrophins and neurotrophins receptors expression in cancer

Neurotrophic signaling has been strongly implicated in cell survival, proliferation and apoptosis (Figure 1). Unbalanced expression of neurotrophins Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin3 (NT3), and/or their receptors Tropomyosin related kinase A (TrkA), Tropomyosin receptor kinase B (TrkB), Tropomyosin receptor kinase C (TrkC), and common Neurotrophin Receptor p75 (p75NTR) have been reported in cancer [36,37]. Increased evidence pinpoints a central role of the neurotrophic pathways in cancer growth and progression. In particular, NGF and BDNF are considered diagnostic biomarkers for hepatic cancer (HC) and CRC. NGF level is 57.3 times higher in CRC than in normal colon tissue [38] and significantly correlates with esophageal squamous cell carcinoma (ESCC) and CRC growth and metastasis [39]. Moreover, NGF overexpression is sufficient per se to induce gastric cancer (GC) in rodent animal models [40]. In line with this, anti-NGF based therapies have been demonstrated to be a promising approach in tumor treatment, as well as in tumor associated cancer pain [41]. Further, inhibition of TrkA blocked tumor growth and reinforced chemotherapy in pancreatic ductal adenocarcinoma (PDAC) [39].

Figure 1. Neurotrophins signaling pathways in cell survival and death. NGF binds TrkA and p75 in a trimeric complex and mediates proliferation, differentiation, and survival via activation of different pathways, like PI3K/AKT, Ras/MAPK and PLC-γ. Upon p75NTR homo-dimerization, NGF is also able to activate NF-κB or JNK, resulting in RIP2 and NRAGE/NRIF signalings, respectively. On the contrary, proneurotrophins, and proNGF in particular, complex with p75NTR and sortilin, leading to activation of pro-apoptotic pathways and cell death.

TrkA, TrkB, and TrkC proteins derive from NTRK1, NTRK2 and NTRK3 genes, respectively. Genetic aberrations of the NTRK genes, like point mutations, gene fusions, constitutively active splice variants are the most well validated oncogenic events in both infantile and adult cancers [42–44]. NTRK1 genetic variants occur in tumors of neuronal type (neuroblastoma and medulloblastoma), but also in non-neuronal cancers, like thyroid, breast, lung, prostate, ESCC, PDAC, GC, HC, and CRC (reviewed in [39,45–48]).

Constitutively active TrkA isoforms generated by alternative splicing rearrangement, like TrkAIII (spliced exons 6, 7 and 9), lack the extracellular signal for membrane localization, induce sustained PI3K/AKT/NF-kB signaling, and cause DNA instability [49]. Oncogenic TrkA fusion products [50] potentiate NGF-dependent carcinogenesis in CRC, thyroid cancer, and AML, leading to the concept of NTRK1 functioning as an oncogene [39]. Treatment of cancers presenting TrkA fusion proteins with selective Trk inhibitors resulted in a better prognosis [51,52]. Further, over-expression of the NGF specific receptor TrkA is considered a reliable index of tumorigenicity, invasiveness, and chemotherapy resistance in several types of squamous cancers [53].

NTRK2 variants have been observed in glioblastoma and HNSC [54]. Also, TrkB overexpression has been observed in ESCC and GC, associated to anoikosis caused by decreased E-cadherin in GC, and to higher chemoresistance in ESCC, being thus considered a metastasis predictor and a strong indicator of bad prognosis [55].

On the contrary, TrkC is a conditional tumor suppressor acting as a dependence receptor and able to induce the caspase cascade in absence of its ligand NT3. NTRK3 is a conditional tumor suppressor epigenetically or genetically downregulated in CRC [56]. Thus, CRC cells characterized by the loss/dysfunctional mutation in the NTRK3 gene acquire a selective advantage and contribute to CRC expansion.

As for the common neurotrophin receptor, p75NTR belongs to the tumor necrosis factor family of receptors. The expression studies on p75NTR led to conflicting results, with p75NTR demonstrated to be a tumor suppressor and a good prognostic factor in digestive cancers or a valuable index of tumor aggressiveness in ESCC and prostatic cancers [39,57–59]. In fact, p75NTR expression is negatively regulated and sometimes null in HC and GC as compared to normal mucosa [60], while its re-activation induces apoptosis through cell cycle arrest, as observed in vitro in HC cells [61]. Moreover, p75NTR is specifically overexpressed in prostate cancer cells, where its level correlates with high-risk prostate tumors with a poor prognosis (Gleason score >7), but not in normal and benign hyperplastic prostate epithelial cells [62]. On the other hand, p75NTR is a marker of chemo-resistant CSCs population in ESCC [59].

Neurotrophins signaling pathway promoting CSCs survival/proliferation

Neurotrophins are regulators of developmental neuronal survival, growth and differentiation and mediate higher-order functions, like synaptic plasticity, learning, memory and behavior in adulthood, after injury, and in age-related neurodegeneration. NGF, BDNF, NT-3, and NT-4/5 are members of the neurotrophin family of growth factors [63,64]. Neurotrophins have preferential binding for specific receptors of the Trk family of receptor tyrosine kinases: NGF binds to TrkA, BDNF and NT-4 to TrkB, and NT-3 to TrkC. All neurotrophins are able to bind the common p75NTR. Further, the association of p75NTR with Trk receptors stabilizes Trk binding to its neurotrophin. Neurotrophin signaling includes Ras, PI3K, Phospholipase C-γ (PLC-γ), and mitogen-activated protein kinase (MAPK) activation leading to survival, proliferation and/or differentiation of target cells. Opposite, activation of p75NTR stimulates NF-κB and c-Jun N-terminal kinase (JNK), promoting inflammation and apoptosis, respectively [65]. In many cancers TrkA activates prosurvival downstream pathways upon NGF binding, while p75NTR binding to its preferred ligand proNGF and co-interactors, like sortilin, instructs pro-apoptotic signaling leading to cell death [66]. In particular, proNGF/p75NTR activates cell death in prostate cells, while their loss in prostate cancer allows tumor expansion and spreading [36]. However, ligand neurotrophins also show ambiguous behavior in carcinogenesis. In line, proNGF binds TrkA and sortilin in breast cancer, inducing the Sex Determining Region Y-box 2 (Sox2) and conferring higher invasiveness to CSCs in a p75NTR-independent manner [67]. Of note, both precursor and mature neurotrophins have been reported to promote tumor growth in breast cancer [68], where p75NTR has been also associated to a pro-survival effect [69].

NGF, BDNF and NT3 pathways represent survival and proliferation signals in CSCs, by activating the Son of Sevenless (Sos)-Ras-MAPK and Fibroblast growth factor receptor substrate 2 (Frs2)/Ankyrin Repeat-Rich Membrane Spanning (ARMS)-Crk pathways, leading to cAMP response element-binding protein (CREB) and NF-kB stimulation, and finally controlling key cellular check-points implicated in CSCs proliferation in glioma, HNSC, melanoma, and breast cancer [37]. BDNF/TrkB and NT3/TrkC signaling complexes have been shown to promote CSCs survival via AKT and Extracellular signal–Regulated Kinases (ERK) pathways in glioma [70]. Further, TrkB deletion in CSCs prevents tumor reappearance in recurrent triple negative breast cancer [71].

NGF survival signaling through the TrkA pathway follows three main routes of intracellular second messengers: 1) Src homology 2 domain containing (Shc)/PI3K/AKT leading to survival of breast and prostate cancers, 2) the Ras/MAPK induced proliferation and invasion in breast and prostate cancer, and cell death by autophagy in medulloblastoma and glioblastoma, 3) PLC-γ/PKC signaling involved in metastasis [36]. Interestingly, signaling via p75NTR strongly depends on binding to its interactors sortilin, Leucine Rich Repeat and Ig Domain Containing 1 (LINGO1), and Neurite outgrowth inhibitor (NOGO), switching from survival to cell death pathways, growth regulation and macrophage clearance, respectively. Indeed, p75NTR via Tumor necrosis factor receptor type 1-associated DEATH domain-dependent (TRADD-dependent), NF-kB and Brain expressed X-linked (BEX) drives a prosurvival effect in breast cancer and schwannoma, while being anti-cancerogenic via JNK-mediated apoptosis in prostate cancer cells and neurons [72–74]. Constitutive active TrkAIII variant induces an undifferentiated stem-like phenotype through increased expression of stemness genes like Nanog, Nestin, Sox2 and CD117, leading to the formation of larger neurospheres in SH-SY5Y neuroblastoma cell line [75]. The NGF-TrkA pathway induces p75NTR proteolytic processing and the release of the soluble p75NTR intracellular domain (ICD), which is central to AKT signaling and CSCs sustained proliferation in several tumor types [76,77], suggesting that the generation of the ICD domain is crucial for the NGF/TrkA pro-oncogenic pathway [39]. Of note, Rho GTPase-mediated recruitment of CD44 to the cell membrane by NGF-TrkA further contributes to CSCs stemness maintenance and survival, resulting in higher tumor aggressiveness [78]. According to this, pharmacological TrkA inhibition prevents p75NTR shedding and the proliferative effect of NGF observed in CSCs. Interestingly, the p75NTR has been observed in the mitotically quiescent CSCs population of the basal epithelia [59,79,80], and activates intracellular signals regulating cell survival, proliferation, and DNA stability, through key oncogenic molecules, like NF-κB [81] and p53 [82]. Furthermore, p75NTR regulates the expression of pluripotency transcription factors, including Sox2, Nanog, and MYC, promotes CSCs self-renewal in breast cancer, and facilitates symmetric divisions in slow-proliferating or quiescent CSCs [83]. The p75NTR neutralization with a specific monoclonal antibody prevents CSCs survival signaling mediated by ERK in HNSC, and genetic loss of p75NTR in melanoma cells completely inhibits tumorigenicity in the xenograft model [84].

Insulin and NGF signalings cross-talk in CSCs metabolism

CSCs expansion and spreading strictly depend on the energy intake by glucose uptake. The insulin/ insulin-like growth factor (IGF) pathway is well known to control glucose uptake in the peripheral organs, as well as in the nervous system. Disturbances in the insulin/IGF pathways have been linked to the pathogenesis of cancer [85]. CSCs stemness maintenance depends on the IGF-1 receptor activation in HNSCC [86]. Accordingly, metformin, the most used drug against insulin resistance in Type 2 Diabetes, has been shown to reduce CSCs reservoir in breast cancer [87]. In particular, the insulin receptor substrate 1 (IRS1)/PI3K/AKT pathway leads to Glycogen synthase kinase 3β (GSK3β) inactivation by serine 9 phosphorylation, thus preventing Snail and Slug proteasome targeting, and activating the NF-kB transcription factor, which in turn increases Snail and Zinc finger E-box-binding homeobox (ZEB) 1 transcription for EMT (reviewed in [88]). Thus, the insulin/IGF pathway induces EMT transcription factors by cross-talking with the signaling platforms implicated in cell proliferation and pluripotency. NGF has been demonstrated to control insulin signaling and improve insulin resistance by promoting glucose uptake in degenerating neurons [89]. Noteworthy, the insulin receptor (IR) signaling has been demonstrated to be transactivated by the NGF receptor TrkA via the IR or the IRS1 in neurons and in the pheochromocytoma cell line PC12 [89,90], and by oncogenic fusion protein Trk-T1 from thyroid carcinoma triggering the IRS-Growth factor receptor-bound protein 2 (IRS-Grb2) complex [91]. Of note, Grb2 and Shc signalings are sufficient per se to induce transformation of fibroblasts [92] and intestinal epithelial cells [93], suggesting Grb-Shc as a crucial molecular hub for common downstream pro-oncogenic pathway. These findings pinpoint a role for the NGF-TrkA/Shc and insulin/IR-IRS axes and reciprocal interplay in the regulation of CSCs glucose metabolism and tumor expansion, highlighting a novel target for precision medicine.

Neurotrophins contribution to CSCs Epithelial-mesenchymal transition

Neurotrophins have been implicated in EMT, a process of genetic reprogramming and morphological shift from elongated epithelial cells to migrating mesenchymal-like cells, with further conversion to CSCs, leading to CSCs enrichment in the tumor microenvironment (TME). Three different transcription factors protein families, the Snail (including Snail and Slug), ZEB (ZEB1, ZEB2), and basic helix–loop–helix (including TWIST1, TWIST2, and TCF3) induce the EMT program by chromatin rearrangement and/or promoter regulation [8]. As a result, proteins of epithelial origin, like E-cadherin, are downregulated and N-cadherin, fibronectin, and vimentin are upregulated to facilitate cell motility and autonomy from niche signals [8,94]. Other EMT transcription factors are common regulator of both CSCs proliferation and EMT commitment, like CD44, Sox2, Sox9, Nanog [8].

In breast cancer, NGF/p75NTR affects epithelial markers like keratin 18, keratin 19 and E-cadherin, while promoting mesenchymal markers, like SLUG, to sustain CSCs migratory behavior [37]. NGF stimulates the expression of SNAIL1, SNAIL2 and TWIST1 in breast cancer cells [68]. Indeed, p75NTR knock-out induces loss of stemness markers, like Sox2 and Sox10, and reconverts spindle-shaped melanoma cells in epithelial-like cells [84]. The p75NTR appears to be involved in EMT phenotypic acquisition and invasiveness. The p75NTR is developmentally expressed in the nervous system and in the neural crest, where it guides fine migration of neural crest cells to form the neural tube. Interestingly enough, the same p75NTR/sortilin signaling system is involved in neural cell migration and cancer metastasis in several tumor types [95].

BDNF/TrkB signaling through AKT and MAPK downstream effectors stimulates the expression of the TWIST-SNAIL axis in rat kidney epithelial cells inducing EMT and CSCs spreading [96]. BDNF through p75NTR activates PI3K/AKT pathway interfering with the RhoA pathway, causing cytoskeletal rearrangement, and promoting CSCs invasiveness in lung cancer, ESCC [97], and head and neck cancer [98]. siRNA silencing or Trk inhibitors prevented BDNF-mediated expression of EMT transcription factors and affected melanoma sphere-forming potential [99].

Angiogenesis in tumor immune evasion

Sufficient blood supply to the tumor comes from neoformation of vessels through endothelial cells angiogenesis and vasculogenesis, as well as by vasculogenic mimicry. CSCs have been observed to be involved in both mechanisms [100]. Interestingly, angiogenic factors overexpressed in many cancers, like Vascular Endothelial Growth Factor (VEGF), Cyclooxygenase 2 (COX-2), and Prostaglandin E2 (PGE2) have an immunosuppressive action, supporting tumor immune evasion. VEGF also inhibits T cell development and is associated with high metastatic potential and poor prognosis in ovarian cancer. COX-2 is implicated in the production of immunosuppressive prostaglandins, like PGE2 and Prostaglandin D2 (PGD2). PGE2 downregulates TNF-α, inhibits T and B cells proliferation, and NK-mediated tumor clearance, while PGD2 favors T helper 2 cells activation at the expenses of tumor eradicating T helper 1 immune response. Also, proangiogenic microRNA (miRNA), like miR-126 sustain cancer metabolism through the IRS1-mediated pathway of glucose uptake [101]. Overall, angiogenesis favors tumor growth by a dual mechanism: on one side facilitating blood supply, on the other side through active suppression of innate and adaptive immune responses. Neurotrophins released by stromal or immune cells in the TME are known to exert a strong proangiogenic effect in in vitro models and in vivo [102–104]. In particular, NGF is known to induce angiogenesis in endothelial cells of several origins through VEGF expression. In line, NGF promotes angiogenesis by TrkA-mediated activation of PI3K and matrix metalloproteinase 2 (MMP2) in breast [105], ovarian [106], hepatocellular [107] cancers. Opposite, proNGF has a net anti-angiogenic effect, increasing angiostatin and thrombospondin-1, and decreasing angiopoietin and angiopoietin-like 1.

Neurotrophins in cholinergic nerve-cancer interplay

Cancer cells growth around nerve terminals and subsequent neural invasion is a process known as perineural invasion (PNI). The presence of nerve endings within the tumors has been described for GC, colon, prostate, breast, pancreatic, bladder, eye cancers [108–112] (reviewed in [113]). Also, neoneurogenesis with the ex novo formation of axons within the tumor has been observed in prostate cancer [114]. Opposite, denervation is known to positively impact on cancer dissemination and patient’s outcome since 1940 in both human and animal studies [115–117]. PNI results from a crosstalk between cancer cells releasing neurotrophins and neuropeptides, and nerve ends expressing TrkA and p75NTR receptors. CSCs respond to NGF by TrkA-mediated autocrine proliferation [118,119] and neurotransmitter release leading to axonal growth around the tumors, tumor expansion and long distance CSCs spreading through the nerves (reviewed in [113]). The neurotrophin family of Trk receptors is well known to support neuron survival and axonal growth in the nervous system, during development and after injury. Similarly to Schwann cells induced axonal regeneration upon nerve injury, NGF, BDNF, NT3 or IGF-II produced by cancer cells sustain cancer growth and PNI through the expression of neurites chemoattractant and guidance molecules associated with poor prognostic outcome (netrin, semaphorins, ephrins, and Slits) [120,121]. NGF, in its precursor or mature form, has been strongly implicated in PNI and neoneurogenesis in prostate cancer [62,122]. Cathecolaminergic, dopaminergic, serotoninergic, glutammatergic, gabaergic, and cholinergic tumor infiltrating nerves have been described so far [123]. In particular, cholinergic nerves within the stem cell-niche help regulate stem cell dynamics in both normal and neoplastic condition [124–126] (reviewed in [40]).

Acetylcholine (Ach) is one of the most important neurotransmitters targeted by cancer pharmacotherapy and its metabolism is dependent upon NGF supply [40]. Nicotine has been indicated as a key driver of tumor cells growth in mesothelioma and colon cancer, and of proliferation, cell migration, and angiogenesis in GC [127]. Nicotine and nicotinic agonists, like 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), lead to human small cell lung cancer (SCLC) proliferation, while the Ach functional antagonist isoproterenol induced growth of lung adenocarcinoma cells [128]. Cholinergic stimulation through muscarinic receptors induces neurotrophic molecules expression [129–131]. Among neurotrophins, NGF was specifically upregulated (20 times higher) by the cholinergic agonist carbachol in GC mouse models, as well as in human GC [40]. A cholinergic/NGF interplay has been reported in GC, with tuft cells-derived Ach inducing NGF release by CSCs expressing the muscarinic receptor 3 (M3R). In turn, the NGF released in the TME promotes nerve growth and further Ach release in a feedback loop sustaining tumor growth and metastasis. In a similar manner, PNI and lymph node spreading is sustained by a catecholamine/NGF axis in PDAC [132]. On the other hand, M3R antagonists inhibited cell growth of non-small cell lung carcinoma (NSCLC) both in vitro and in vivo [133]. Indeed, the increase of cholinergic parasympathetic fibers by neurogenesis and axonogenesis in prostate cancer xenografts model correlates with metastasis [134]. Similarly, proNGF favors tumor infiltration and affects patient’s survival in human prostate cancer [62].

Taken together, these findings strongly pinpoint the neurotrophin/Trk signaling as messengers between nerves and cancer cells, driving peritumoral innervation and consequent tumor growth and dissemination.

Neurotrophins and exosomes-driven tumorigenesis

Tumors release extracellular vesicles, called exosomes, regulating the TME and promoting disease progression by induction of tumor tolerance and spreading, and axonogenesis (reviewed in [135]). Exosomes are 30–150 nm vesicles expressing marker proteins, such as CD63, Alix, Tsg, CD9, and CD81, and delivering cargo of intercellular messenger proteins, mRNA, non-coding RNA like long non-coding RNA (lncRNA), miRNA, DNA, and lipids [136]. Exosomes facilitate intratumoral axon growth by releasing axonal guidance molecule, like EphrinB1 [136]. Indeed, tumors compromised in exosome release are less innervated than controls and pharmacological blockade of exosome release by the multi-vesicular body (MVB) inhibitor GW4869 is effective in diminishing tumoral innervations by β-III tubulin positive “nerve twigs” [136]. Opposite, exosomes from “non-metastatic” melanoma are able to trigger NK and TRAIL-driven macrophage clearance of tumor cells, reinforcing immune surveillance at the pre-metastatic niche and exerting a pro-apoptotic effect on lung carcinoma cells [137]. Of note, neuronal exosomes are enriched with p75NTR [138], and prostate cancer exosomes carry tyrosin kinases, such as Src tyrosine kinase and IGF-1R, promoting tumor expansion and angiogenesis [139,140]. Furthermore, the BDNF receptor TrkB transfers glioblastoma aggressiveness to recipient cancer cells [141]. CSCs exosomes from a CSCs clonal line transfer SLUG and Sox2 and induce EMT through lnc-Regulator of Reprogramming (lnc-ROR) [142]. Plus, exosomal transfer of miRNA-142 from bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) stimulates colon CSCs proliferation by NUMB-mediated activation of Notch signaling [143]. Thus, active signaling molecules are transported by cancer exosomes contributing to CSCs communication with the TME and modulating cancer outgrowth metastasis and immune cells evasion. Additionally, CSCs exosomes are potential nano-carriers for drugs and vaccines, and their cargos provide potential biomarkers for early diagnosis and improved prognosis in cancer.

Conclusions

Taken together, the experimental findings here reported suggest opposite pro-oncogenic and anti-oncogenic actions of the NGF signaling pathway in the control of CSCs growth and cancer evasion from the host immune system (Figure 2). NGF/TrkA signaling and cholinergic innervation of the tumor niche take central stage in tumor initiation and progression, as well as metastatic spreading. In line with this, the targeting of neurotrophic growth factors in cancer has been suggested to halt tumor progression through direct CSCs targeting, to achieve control of nerve infiltration and angiogenesis, and minimize cancer pain [182–184]. Accordingly, selective and in situ treatment with potent Trk kinase inhibitors, clinical development of drugs targeting NTRK genetic rearrangement combined with canonical cancer therapy, and/or novel encouraging CAR-T immunotherapy are all promiseful neurotrophin-based strategies to improve cancer patients outcome.

Figure 2. The pro-oncogenic and anti-oncogenic effects of the NGF signaling pathway in CSC metabolism and EMT. Schematic model illustrating the opposite pro-oncogenic (left) and anti-oncogenic (right) actions of NGF signaling pathway in the control of CSCs growth and cancer evasion from the host immune system. Pro-oncogenic pathway. CSCs promote tumor growth, perineural invasion, CSCs proliferation and spreading through vessels and nerves by NGF release. In fact, tumor-released NGF attracts cholinergic endings and promotes cancer expansion and neoangiogenesis through neuronal-derived Ach and VEGF. Further, CSCs inhibit the host immune response and facilitate metastatic spreading through IL-10, IL-6, and TGF-β. Excess amount of proNGF stimulates macrophages polarization toward the M2 phenotype, giving rise to TAMs, which are unable to phagocytize cancer cells. Moreover, MDSCs induce Tregs expansion by TGF-β release and contribute to dismount the T-cells mediated immune response. Anti-oncogenic pathway. On the other hand, increasing evidences pinpoint a role for NGF pathway in promoting tumor surveillance by both natural and adaptive immune cells. The NGF-TrkA signaling system induces phagocytic M1 macrophages, thus resolving cancerogenic inflammation. Moreover, NGF receptors allow membrane exposure of activatory NK receptors. The p75-expressing γδ T cells are phagocytic T cells of the so-called “lymphoid stress surveillance” system. NGF-TrkA promotes MHC-I and MHC-II expression by cancer cells and CSCs, and allow recruitment of IL-2 activated T cells in lymph- , promoting the tumor mass eradication. The illustration includes images modified from “freevector.com”, distributed under the Creative Commons Attribution 4.0 license (CC BY 4.0).

Nonetheless, increasing evidences pinpoint the involvement of neurotrophins, and specially NGF, in tumor immune surveillance through cytokines-driven modulation of the innate and acquired immune system cells. In particular, given the Tregs and PD1 control by p75NTR and NGF, NGF pathway inhibition would result in immune tolerance induction, thus challenging the use tout-court of TrkA inhibitors to dampen tumor growth. Moreover, the activation of the neurotrophic pathway is fundamental in order to downregulate oncogenic inflammation during self-promoted tumor growth. To overcome this dichotomy, fine understanding of the molecular targets and cellular substrates of NGF/TrkA involved in tumor growth on one side and immune surveillance on the other side is demanding nowadays in order to design selective and coordinated therapies against tumor characterized by uncontrolled overactivation of the NGF pathway as oncogenic driver.

Abbreviations

AML: Acute Myeloblastic Leukaemia; APCs: Antigen-Presenting Cells; BCL-2: B-cell lymphoma-2; BCL-XL: B-cell lymphoma-Extra Large; ICI: co-Inhibitory Immune Checkpoints; CTL: Cytotoxic T Lymphocytes; CTLA-4: Cytotoxic T-Lymphocyte Antigen-4; CTCs: Circulating Tumour Cells; CSCs: Cancer Stem Cells; DCs: Dendritic Cells; EMT: Epithelial-Mesenchymal Transition; GC: Gastric Cancer; HNSC: Head and Neck Squamous Carcinoma; MCSF: Macrophage Colony-Stimulating Factor; MDSC: Myeloid-Derived Stem Cells; MHC: Major Histocompatibility Complex; NSCLC: Non-Small Cell Lung Carcinoma; PDL1: Programmed Death-Ligand 1; PGE2: Prostaglandin E2; SCLC: Small Cell Lung Cancer; TAMs: Tumour Associated Macrophages; Tregs: Regulatory T cells; IGF: Insulin-like Growth Factor; NGF: Nerve Growth Factor; NT: Neurotrophin; VEGF: Vascular Endothelial Growth Factor; P75NTR: p75 neurotrophic receptor; TrkA: Tropomyosin related kinase A; TrkB: Tropomyosin related kinase B; TrkC: Tropomyosin related kinase C; BEX: Brain Expressed X-linked; COX-2: Cyclooxygenase-2; CREB: cAMP Response Element-Binding protein; DAMP: Danger Associated Molecular Patterns; IDO: Indoleamine 2,3-Dioxygenase; INF- γ: Interferon-γ; LINGO1: Leucine Rich Repeat And Ig Domain Containing 1; JNK: c-Jun N-terminal kinases; mTOR: mammalian Target Of Rapamicin; MAPK: Mitogen-Activated Protein Kinase; MVB: Multi-Vesicular Body; NOGO: Neurite Outgrowth inhibitor; NF- kB: Nuclear Factor- kB; NLR: Nod-like Receptor; PI3K: phosphatidylinositol 3-kinase; PLC-γ: Phospholipase C-γ; PRR: Pattern Recognition Receptor; STAT3: Signal Transducer and Activator of Transcription-3 (STAT-3); TLR: Toll Like Receptor; TEM: Tumor Micro Environment; TRADD: Tumor necrosis factor receptor type 1-associated DEATH domain-dependent; TRAL: TNF-related apoptosis-inducing ligand.

Conflicts of Interest

The authors declare that they have no conflicts of interests.

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