Contributions of neuroimmune interactions to chemotherapy-induced peripheral neuropathy development and its prevention/therapy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating sequela that is difficult for both clinicians and cancer patients to manage. Precise mechanisms of CIPN remain elusive and current clinically prescribed therapies for CIPN have limited efficacy. Recent studies have begun investigating the interactions between the peripheral and central nervous systems and the immune system. Understanding these neuroimmune interactions may shift the paradigm of elucidating CIPN mechanisms. Although the contribution of immune cells to CIPN pathogenesis represents a promising area of research, its fully defined mechanisms have not yet been established. Therefore, in this review, we will discuss (i) current shortcoming of CIPN treatments, (ii) the roles of neuroimmune interactions in CIPN development and (iii) potential neuroimmune interaction-targeting treatment strategies for CIPN. Interestingly, monocytes/macrophages in dorsal root ganglia; microglia and astrocytes in spinal cord; mast cells in skin; and Schwann cell near peripheral nerves have been identified as inducers of CIPN behaviors, whereas T cells have been found to contribute to CIPN resolution. Additionally, nerve-resident immune cells have been targeted as prevention and/or therapy for CIPN using traditional herbal medicines, small molecule inhibitors, and intravenous immunoglobulins in a preclinical setting. Overall, unveiling neuroimmune interactions associated with CIPN may ultimately reduce cancer mortality and improve cancer patients’ quality of life.

1. Introduction

Chemotherapy is one of the most common first-line treatments for cancer patients. Despite great success in eradicating cancer, it has also been known to cause serious side effects, since it also targets normal cells, which are dividing rapidly (e.g., blood cells, hair cells, intestinal mucosa). Thus, the majority of its side effects include pancytopenia, hair loss, and gastrointestinal issues such as nausea, vomiting, and diarrhea [1]. Importantly, chemotherapy can also damage the nervous system, resulting in fatigue, pain, cognitive impairment, and peripheral neuropathy [2]. Chemotherapy-induced peripheral neuropathy (CIPN) is often described as a “glove and stocking” neuropathy, since symptoms are often felt in the hands and feet [3]. It is characterized as (i) a gain of sensory neuronal function, where patients experience sensations of “pins and needles”, tingling, neuropathic pain; (ii) a loss of sensory function, where symptoms are numbness, dulled sensation, and a loss of vibratory sense; or (iii) a combination of both a loss and gain of sensory function [2]. Platinum-based drugs, taxanes, vinca alkaloids, bortezomib, and thalidomide are known to be associated with CIPN development [4].

A meta-analysis of 4,179 adult cancer patients receiving chemotherapy revealed that 68% of them developed CIPN after 1 month of chemotherapy treatment (either: oxaliplatin, paclitaxel, cisplatin, bortezomib, thalidomide, vincristine or a combination) (defined as acute CIPN), while 30% of them had CIPN at 6 months and beyond (defined as chronic CIPN) [5]. In most cases, CIPN resolves spontaneously; however, in some cases, CIPN symptoms persist, and it becomes chronic. One of the persistent pathologic findings observed in chronic CIPN patients is intraepidermal nerve fiber (IENF) loss in hands and feet [6]. Such sensory nerve fiber loss and subsequent loss of sensory functions (e.g., numbness) lead to reduced quality of life and potential risk of injury. Indeed, patients with CIPN are at a nearly three times higher risk of fall [7]. Moreover, when CIPN presents in severe cases and/or is irreversible, it leads to dose-reduction or premature treatment cessation, resulting in increased mortality [8]. Due, in part, to increased morbidity and mortality rates, the average healthcare costs are approximately $17,000 higher for patients with CIPN than those without CIPN [9], which adds a financial burden for patients and their families.

While hypothesis-driven studies have revealed various CIPN mechanisms, including changes within both transient receptor potential channels [e.g., transient receptor potential cation channels: subfamily V member 1 (TRPV1), subfamily A, member 1 (TRPA1)] and ion channels (e.g., calcium, potassium, and sodium channels) as well as mitochondrial dysfunction [10, 11], few clinically effective therapies exist for CIPN. Although duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine [12], has been reported to decrease CIPN symptoms in patients receiving oxaliplatin or paclitaxel, supportive evidence for its positive efficacy has been limited, and mechanisms of action of this drug on CIPN have not been well characterized [13]. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline) for cisplatin and paclitaxel-neuropathy and anticonvulsants (e.g., gabapentin) have also been used to treat CIPN (taxanes-paclitaxel or docetaxel; platinum compounds-carboplatin or cisplatin or oxaliplatin; vinca alkaloids-vincristine or vinblastine) [14, 15]. However, only limited efficacy for prevention and alleviation of CIPN has been demonstrated [14, 15].

For the past several years, the involvement of immune cells in the CIPN pathogenesis has been appreciated. The infiltration of monocytes into the sites of injury and inflammation after chemotherapy has been thought to cause the development of mechanical allodynia, resulting in CIPN in animal studies of paclitaxel [16]. Similarly, in additional preclinical studies the infiltration of macrophages into dorsal root ganglion (DRG) during chemotherapy treatments has been shown to lead to increased paclitaxel-induced neuropathic pain behavior (i.e., mechanical allodynia or reduced paw withdrawal threshold) [17]. Conversely, the infiltration of T cells into DRGs has been demonstrated to be a part of the resolution of CIPN behaviors (mechanical allodynia) in animal studies of cisplatin and paclitaxel [18, 19]. Further, immune cell-associated cytokines or chemokines have also been associated with the CIPN pathogenesis. Indeed, monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) are involved in the development of CIPN associated with paclitaxel [20, 21], whereas IL-10 is known to be implicated in CIPN resolution originally induced by paclitaxel and oxaliplatin [22, 23]. Moreover, in preclinical models, targeting IL-20 [24] or tumor-necrosis factor-alpha (TNF-α) [25] has been tested as treatment for paclitaxel-induced peripheral neuropathy.

Although the contribution of immune cells to CIPN pathogenesis represents a promising area of research, its fully defined mechanisms have not yet been established. Additionally, a comprehensive review of this area can be useful for developing much needed intervention for CIPN. Therefore, in this review, we will discuss (i) current shortcoming of CIPN treatments, (ii) the roles of neuroimmune interactions in CIPN development and (iii) potential neuroimmune interaction-targeting treatment strategies for CIPN.

2. Current state of CIPN treatments

Although many advances in understanding the mechanisms of CIPN have developed over the past several years, most currently available treatments for CIPN do not have a significant impact on improving these symptoms. Furthermore, because the mechanism of cancer-killing of each chemotherapeutic agent known to induce CIPN differs, it is logical to infer that the mechanism of CIPN development may also differ. Thus, defining a generalized treatment for CIPN has proven difficult. Currently, duloxetine is the only American Society of Clinical Oncology recommended agent for treatment of painful CIPN symptoms in patients receiving oxaliplatin or paclitaxel [26]. However, a recent report has shown that its benefits in both (i) CIPN treatment (Risk Ratio (RR) 0.92, 95% Confidence Interval (CI) 0.84 to 1.01) and (ii) CIPN prevention (RR 1.02, 95% CI 0.87 to 1.19) are statistically similar to those of placebo treatment [27]. Further, several side effects (e.g., nausea, reduced appetite, constipation, drowsiness or insomnia) and high cost potentially preclude long-term use of this drug [28].

Alternatively, tricyclic antidepressants (e.g., amitriptyline, nortriptyline), anticonvulsants (e.g., gabapentin), and opioids (e.g., oxycodone) have been repurposed for treating CIPN [29], however, their benefits are controversial. Indeed, in a stage III clinical trial of 51 cancer (lung, ovarian, and other unspecified cancer) patients exhibiting cisplatin-induced peripheral neuropathy, treatment with nortriptyline failed to show any beneficial effect on pain or paresthesia [30]. Further, use of tricyclic antidepressants as a treatment for CIPN is not common due to their lack of established benefits and risk of adverse side effects, such as constipation, dizziness, cardiac arrhythmias, or tachycardia [26, 29, 31]. In a phase III randomized, double-blind, placebo-controlled study, comparing treatment effects between gabapentin and placebo for CIPN, of 115 cancer (unspecified) patients receiving either taxanes (paclitaxel or docetaxel), platinum compounds (carboplatin, cisplatin, or oxaliplatin), or vinca alkaloids (vincristine or vinblastine), there was no significant difference in average pain score between two groups (3.3 gabapentin vs. 3.1 placebo, p = 0.8) [32]. Conversely, a phase IV clinical study, investigating the effect of gabapentin on CIPN in 72 cancer (respiratory, digestive, urinary/reproductive, head and neck) patients treated with either taxanes, platinum compounds, a combination, or unspecified chemotherapy demonstrated that gabapentin in combination with oxycodone/naloxone significantly reduced pain intensity score from baseline [6.0 ± 1.3 (mean ± standard deviation) to week 4 (4.7 ± 2.1, p < 0.0001) [33]]. Consistent with this notion, a recent systematic review revealed a disparity in the literature regarding the treatment efficacy of gabapentin on CIPN [34].

Similarly, opioid use for CIPN has been investigated in clinical studies. In an open-label, multi-center, observational study of 46 patients with hematological malignancy that were prescribed bortezomib, it was found that controlled-release oxycodone led to an 76.5% overall reduction in the numerical rating scale of pain intensity (p < 0.002) after 14 days of treatment [35, 36]. Although somewhat effective on CIPN, opioids are not currently offered as the standard first-line treatment for CIPN, since they can cause risk for dependence, addiction, sedation, dysphoria, nausea, vomiting, hypotension, constipation, or respiratory depression [37, 38]. Indeed, in a retrospective study of 64 colorectal cancer patients that underwent FOLFOX therapy (oxaliplatin to a regimen of bolus and continuous-infusion 5-fluorouracil combined with leucovorin) and received controlled-release oxycodone (n = 29), there were 15 possible adverse events that were associated with opioid use, such as anorexia, constipation, and even hallucination [39].

Another promising treatment for pain relief in CIPN patients is a capsaicin patch [40]. In a single center, open-label, longitudinal study of 16 patients with different cancer types (e.g., colon, multiple myeloma, lung, or ovarian receiving chemotherapy (platinum, taxane, and proteasome inhibitor compounds), when 8% capsaicin patches were locally placed on their hand and foot, there was (i) significant reduction of spontaneous pain, (ii) significant reduction of cold-evoked pain, and (iii) significant increase of the reduced IENF (known to be decreased in CIPN patients) [41]. While results from this study have a potential implication for CIPN treatment, further large-scale studies are clearly warranted.

Besides medication treatment, complementary approaches have also been used as treatment options for CIPN. A multicenter, randomized controlled trial showed 6 weeks of exercise [(i)walking: moderately intense aerobic exercise and (ii) resistance bands: low to moderate-intensity resistance exercise] significantly reduced hot/cold sensitivity in hands/feet of breast cancer patients without metastasis receiving taxane-, platinum-, or vinca alkaloid-based drugs, when compared to patients who received the same chemotherapy regimen but without exercise [42]. However, the exercise failed to improve numbness and tingling sensation in these patients [42]. Further, a meta-analysis regarding the therapeutic effects of exercise in patients with neuropathies (e.g., CIPN, diabetic peripheral neuropathy, idiopathic axonal polyneuropathy, and inflammatory neuropathies) revealed that a significant improvement in neuropathy symptoms of CIPN patients with exercise interventions was observed, compared to CIPN patients without exercise (Z-score = 2.00, p < 0.05) [43]. Interestingly, another meta-analysis revealed that acupuncture treatments lead to significant improvements in both pain [pain scores: −1.21, 95% confidence interval (CI) = −1.61 to −0.82, p < 0.00001] and nervous system symptoms (The Functional Assessment of Cancer Therapy/Neurotoxicity questionnaire scores: −2.02, 95% CI = −2.21 to −1.84, p < 0.00001) of 386 patients with CIPN from platinum, taxane, bortezomib, vinblastine-etoposide, or vinca-alkaloids [44]. Despite these recent successes of acupuncture for CIPN treatment, the physiological and molecular mechanisms whereby acupuncture relieves CIPN symptoms remain elusive [43, 44].

Despite its negative impacts on patient quality of life and survival, little is known about the precise mechanisms underlying CIPN, and very few clinically effective therapies exist for CIPN. Therefore, new, and effective treatments for CIPN are urgently needed.

3. Neuroimmune Interactions in CIPN

Neuroimmune interactions have become increasingly recognized in the pathobiology of CIPN. However, currently available treatments for CIPN rarely target neuroimmune interactions. This might be one of the reasons why these treatments fail to attenuate/prevent CIPN, suggesting that studies of neuroimmune interactions may pave the way to develop more effective CIPN therapies. In order to do so, precise mechanisms of how immune cells and neurons interact must first be elucidated. DRG sensory nerve fibers extend to the periphery of the body and are known to interact with immune cells. Both innate and adaptive immune responses following nerve injury have been proposed to be involved in the development of neuropathic pain [45]. Similarly, several different types of immune cells have been implicated in CIPN development [46]. Moreover, it has been suggested that the chemotherapy itself influences the neuroimmune interactions [47]. Indeed, Gene Ontology analysis on RNA sequencing data of DRG obtained from paclitaxel-treated rats showed that immune response pathways (e.g., myeloid leukocyte activation and immune response-regulating signaling pathway) were downregulated, while the same analysis on DRG obtained from oxaliplatin-treated rats revealed that pathways related to neurofilament, mitochondria, and lipid assembly or regulation were downregulated [47]. However, how the chemotherapeutic agents impact immune cells and contribute to the neuroimmune interactions, resulting in the development of CIPN, remains elusive.

It has been demonstrated that in a preclinical mouse study, vincristine enhanced vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells, and these adhesion molecules were responsible for the infiltration of F4/80⁺ monocytes/macrophages into the sciatic nerves [48]. These infiltrating monocytes/macrophages produced reactive oxygen species (ROS) by binding to endothelial cell-derived C-X3-C motif chemokine ligand 1 (CX3CL1) through C-X3-C motif chemokine receptor 1 (CXCR1) [48]. The resulting ROS activated transient receptor potential ankyrin 1 (TRPA1) receptor on the sciatic nerve, resulting in increased vincristine-mediated mechanical allodynia [48]. Moreover, when monocytes/macrophages were chemically depleted with clodronate, vincristine-mediated mechanical allodynia was reduced [48]. Similarly, in rats treated with paclitaxel, significant increased mechanical allodynia through the upregulation of CX3CL1 in A-fiber primary sensory neurons, as well as infiltration of macrophages into DRG were observed [49]. The paclitaxel-induced mechanical allodynia and macrophage infiltration were blocked with CX3CL1 neutralizing antibody [49]. Surprisingly, when CXCR1-knockout mice were treated with vincristine, these mice still developed mechanical allodynia [50]. However, when these vincristine-exposed CXCR1-knockout mice were treated with C-C Motif Chemokine Receptor 2 (CCR2) antagonist, significant reduction in the development of mechanical allodynia and F4/80⁺ monocyte infiltration into the sciatic nerve were observed, suggesting the interaction between CXCR1 and CCR2 [50]. Similarly, when rats were treated with either paclitaxel [16] or oxaliplatin [21], increased levels of CCR2 and its ligand monocyte chemoattractant protein-1 (MCP1) were detected in their DRGs, resulting in increased mechanical hypersensitivity and decreased IENFs. In both cases, when animals were treated with intrathecal anti-MCP1 antibody to block the MCP1/CCR2 interaction, chemotherapy-induced mechanical hypersensitivity and loss of IENFs were reversed [16, 21]. Although, in these studies, monocyte/macrophage infiltration in DRGs were not investigated, these findings suggest that their infiltration into DRGs might be a potential mechanism of paclitaxel- or oxaliplatin-induced peripheral neuropathy development, since MCP1 is well-known for the recruitment of monocyte/macrophage into damaged tissue [51]. Indeed, in the DRG of rats with paclitaxel-induced mechanical allodynia, higher numbers of CD68+ macrophages were observed through toll-like receptor 4 (TLR4) activation followed by the increased expression of MCP1 in DRGs, compared to vehicle-treated rats [17]. Additionally, the infiltration of CD68+ macrophages into DRG after paclitaxel treatment was also associated with significant upregulation of necroptosis-related proteins, receptor-interacting protein kinase, and mixed-lineage kinase domain-like protein, in DRG, and these protein upregulations was inhibited with macrophage scavenging agent, clodronate disodium [52]. Moreover, in the DRG of mice with oxaliplatin-induced mechanical allodynia, increased levels of MCP1 and metalloproteinase-9/2 (MMP-9/2) were found, compared to mice treated with vehicle [53]. Interestingly, oxaliplatin-induced mechanical allodynia were significantly reduced in mice treated with MMP-9 inhibitor and in MMP-9 knockout mice [53]. Further, clodronate liposome treatment prior to oxaliplatin administration significantly attenuated oxaliplatin-induced mechanical allodynia by reducing MMP-9/2 levels in the DRG [53].

Additionally, in the sciatic nerves of mice treated with paclitaxel, elevated ionized calcium binding adapter molecule 1 (Iba1)-positive macrophage infiltration, and increased levels of galectin-3 in Schwann cells and plasma were observed [54]. When galectin-3 deficient mice were treated with paclitaxel, significantly less macrophage infiltration in the sciatic nerve and reduced mechanical hypersensitivity were seen, compared to those of paclitaxel-treated wild type mice [54]. Consistent with this finding, plasma galectin-3 levels were significantly higher in breast cancer patients with taxane (paclitaxel or docetaxel)-induced peripheral neuropathy than those without peripheral neuropathy [54]. Similarly, paclitaxel treatment increased serum interleukin-20 (IL-20) and CD68 positive macrophage infiltration in the DRGs of mice with increased mechanical allodynia and thermal hypoesthesia [24]. Interestingly, these infiltrated macrophages expressed higher levels of IL-20 receptors, and pre-treatment with intraperitoneal injection of anti-IL-20 neutralizing monoclonal antibody attenuated paclitaxel-mediated mechanical allodynia, thermal hypoesthesia, and macrophage infiltration into the DRGs [24]. Moreover, increased serum IL-20 levels in female ovarian cancer or endometrial cancer were associated with increased CIPN risk (n = 15 cancer patients) [24].

Interestingly, it has been suggested the effects of DRG-infiltrated macrophages on CIPN development is associated with sex differences. Indeed, paclitaxel induced mechanical allodynia in wild mice coincident with increased macrophage infiltration into the DRGs. These macrophage-associated paclitaxel-induced mechanical allodynia was compromised only in male TLR9-deficient mice, whereas there were no changes in paclitaxel-induced mechanical allodynia in female TLR9-deficient mice [55]. Importantly, TLR9 deficiency did not alter macrophage infiltration between two sexes [55].

Microglia are central nervous system-resident immune cells, and its functions are thought to be similar to peripheral macrophages [56]. During CIPN development, microglia accumulate into the spinal cord and are activated. In the spinal cord of cisplatin-treated rats with mechanical and cold allodynia, P2Y12 receptor was upregulated in the spinal cord microglia along with the activation of IBA-1/Src family kinase (SFK)/p38 pathway and the production of IL-18 [57]. When these rats were treated with P2Y12 inhibitor, the activation of IBA-1/Src family kinase (SFK)/p38 pathway, the production of IL-18 of spinal cord microglia, and cisplatin-mediated mechanical and cold allodynia were diminished [57]. Furthermore, IL-18 binding protein reversed the activation of IBA-1/Src family kinase (SFK)/p38 pathway, and cisplatin-mediated mechanical and cold allodynia [57]. Similarly, in the spinal cord of mice displaying cisplatin-induced mechanical allodynia, the activation of microglia, but not astrocytes, was observed [58]. In addition, cisplatin enhanced triggering receptor expressed on myeloid cells 2 (TREM2) expression in spinal cord microglia, and neutralizing antibody against TREM2 attenuated cisplatin-induced mechanical allodynia in these mice [58]. Additionally, anti-TREM2 neutralizing antibody suppressed the mRNA expression of IL-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and CD16 mRNA in the spinal cord (mediated by cisplatin treatment), but up-regulated the anti-inflammatory cytokines, IL-4 and IL-10 [58].

Interestingly, CIPN-related microglia accumulation in the spinal cord may be regulated by gut microbiota. In the spinal cord of mice that developed paclitaxel-induced peripheral neuropathy (mechanical, heat, or cold sensitivity), the accumulation of microglia was observed [59]. When the gut microbiota was depleted with antibiotic treatment, the accumulation of microglia as well as paclitaxel-induced peripheral neuropathy behaviors were diminished [59]. Further, when fecal transplantation of the mouse strain, which developed paclitaxel-induced peripheral neuropathy above, was performed into a mouse strain, which has resistance to paclitaxel-induced peripheral neuropathy, paclitaxel treatment induced the accumulation of microglia into the spinal cord and paclitaxel-induced peripheral neuropathy in these transplanted mice [59]. In the gut of mice with paclitaxel-induced peripheral neuropathy, decreased abundance of Akkermansia muciniphila was observed, suggesting that this bacteria strain may be responsible for the protection for paclitaxel-induced peripheral neuropathy and spinal microglia accumulation [59].

Despite the evidence above, the contribution of microglia to CIPN development has been controversial. Indeed, two rat studies found that treatments with paclitaxel, oxaliplatin and bortezomib, which induced CIPN, activated astrocytes (nervous system glial cells), but failed to activate microglia in their spinal cord [60, 61]. In addition, minocycline treatment, known to prevent CIPN behaviors, inhibited chemotherapy-induced astrocyte activation and peripheral neuropathy [60, 61]. Interestedly, the damage of spinal astrocytes is involved in the development of CIPN. When mice were treated with oxaliplatin, the levels of insulin-like growth factor-1 (IGF1), known to maintain nerve survival, in spinal astrocytes were down-regulated, and animals developed mechanical hypersensitivity [62]. However, when mice were administered recombinant IGF1 intrathecally or intraperitoneally, oxaliplatin-induced peripheral neuropathy behaviors were attenuated [62].

In the skin of mice with oxaliplatin-induced mechanical allodynia, the number of mast cells and their degranulation were increased [63]. Topical treatment of mast cell stabilizer attenuated oxaliplatin-induced mechanical allodynia, decreased the degranulation of mast cells, but did not change the number of mast cells [63]. Additionally, oxaliplatin-induced mechanical allodynia was diminished in both mast cell knock-out mice and administration of an antagonist for proteinase-activated receptor 2 (PAR2, a receptor for a major mast cell-derived inflammatory serine protease, tryptase) [63]. Additionally, when rats and mice with paclitaxel-induced mechanical allodynia and heat hyperalgesia were treated with quercetin (a polyphenolic flavonoid, known as a mast cell stabilizer [64]), these paclitaxel-induced behaviors were reversed by blocking histamine release from mast cells [65]. Quercetin also reduced the expression of transient receptor potential cation channel subfamily V member 1 (TRPV1) and protein kinase C epsilon isoform (PKCε) in both the spinal cord and DRG, suggesting paclitaxel induces CIPN through the activation of TRPV1 and PKCε in the spinal cord and DRG by enhancing histamine release from mast cells [65].

Schwann cells are known to support the axon regeneration [66] and thought to be involved in immunoregulation by recruiting macrophages into damaged nerves [67]. When mice were treated with three different microtubule-targeting agents (MTAs) eribulin, ixabepilone, and paclitaxel, which are known to induce CIPN [68, 69], longer-lasting morphological changes in sciatic nerves (e.g., axon area density, frequency of myelin abnormalities), and higher number of Schwann cells within sciatic nerves were observed in paclitaxel-treated mice, compared to eribulin- or ixabepilone-treated mice, suggesting that Schwann cell interfere with the recovery of damaged nerves [70]. Further, paclitaxel treatment induced dedifferentiation of Schwann cells into an immature state by increasing the extracellular domain of neurotrophin receptor p75 and galectin-3 in murine sciatic nerves, suggesting that Schwann cell differentiation is in part responsible for nerve protection from chemotherapeutic insults [71]. Indeed, in a mouse study, the phosphodiesterase (PDE) 3 inhibitor cilostazol, which inhibits the dedifferentiation of Schwann cell, reduced paclitaxel-induced mechanical allodynia as well as p75 and galectin-3 sciatic nerves [72]. Interestingly, in the VISTA phase 3 trial of 139 myeloma patients treated with bortezomib– melphalan–prednisone [73], 2016 single-nucleotide polymorphisms (SNPs) were identified and after using a false discovery rate (FDR) of less than 0.05, two SNPs were found to be significantly associated with time to onset of at least grade 3 bortezomib-induced peripheral neuropathy. One of these SNPs found to be significant was Gap junction protein epsilon 1 (GJE1) [FDR = 0.041, Hazard Ratio with 95% Confidence Interval 20.0 (5.0–88.3)] which is known to be involved in reflexive coupling within Schwann cells [73]. This study suggested that bortezomib induces peripheral neuropathy by enhancing demyelination through the induction of GJE1 variants, although demyelinating features in bortezomib-induced peripheral neuropathy is clinically uncommon [73].

As stated above, most of the cells associated with the immune system are involved in the development of CIPN. However, interestingly, T cells are thought to play a crucial role in the resolution of CIPN. Indeed, when T-cell deficient mice were treated with paclitaxel, paclitaxel-induced mechanical allodynia was prolonged, compared to wild type mice, although the severity of CIPN behaviors did not differ between two groups [19]. When T-cell deficient mice were reconstituted with CD8⁺ T cells, the length of paclitaxel-induced mechanical allodynia was normalized by increasing IL-10 receptor in DRGs [19]. Further, IL-10 was neutralized with intrathecal injection of anti-IL-10 antibody, the paclitaxel-induced mechanical allodynia in (i) wild type mice or (ii) T-cell deficient mice reconstituted with CD8⁺ T cells were delayed from recovery [19]. Additionally, paclitaxel-induced mechanical allodynia was prolonged in IL-10 knock-out mice, and endogenous treatment of IL-10 attenuated paclitaxel-induced mechanical allodynia in T-cell deficient mice [19]. Similarly, when (i) T-cell deficient mice were reconstituted with CD8+ T cells derived from IL-13 deficient mice or (ii) wild type mice were treated with anti-IL-13 antibody, there was resolution of cisplatin-induced mechanical allodynia and IL-10 production from macrophages; thus, suggesting that the source of IL-10, which is in part responsible for CIPN resolution, is macrophages and this IL-10 production from macrophages is stimulated by T cells through IL-13 [18]. Interestingly, when T cells from wild type mice were exposed to cisplatin prior to reconstitution into T-cell deficient mice, mechanical allodynia mediated by either cisplatin or paclitaxel was prevented and resolved, suggesting that the impact of T-cell education on CIPN resolution is not cisplatin dependent [74].

4. Potential Neuroimmune Interaction-targeting treatments for CIPN

Despite the long-term efforts on investigating the mechanisms of CIPN and developing prevention and treatment strategies for CIPN, current treatments for CIPN do not have a significant impact on precluding or improving CIPN. As stated above, the contributions of neuroimmune interactions to CIPN development have recently been appreciated. Consequently, the therapeutic approaches that target neuroimmune interaction, especially targeting immune cells, have recently been tested in preclinical levels.

In an oxaliplatin-induced peripheral neuropathy mouse study, oxaliplatin caused mechanical and cold allodynia by activating inducible nitric oxide synthase (iNOS), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated nuclear factor-kappa B (p-NF-κB) expression in the spinal microglia [75] and NF-κB p65 in DRG [76]. Since a medicinal herb, syringaresinol (a phytochemical from the bark of Cinnamomum cassia) is known to reduce inflammation by directly affecting microglia and macrophages [77, 78], these animals were treated intrathecally with this medicinal herb [75]. As expected, syringaresinol treatment attenuated oxaliplatin-induced mechanical and cold allodynia by down-regulating microglial iNOS, p-ERK, and p-NF- κB [75]. Similarly, intrathecal injection of another medicinal herb, apigenin [a trihydroxyflavone found in vegetables, fruits, and herbal plants and known to prevent microglia-mediated inflammation [79]] attenuated paclitaxel-induced heat allodynia and hyperalgesia by (i) reducing the levels of TNF-α and IL-1βa in spinal microglia; (ii) activating nuclear factor erythroid 2-related factor 2 (NRF2)/Antioxidant Response Element (ARE) signaling pathway in spinal microglia; and (iii) inducing microglial polarization to anti-inflammatory phenotypes [80]. Additionally, intrathecal injection of Trimethoxyflavanone [a derivative of Naringenin, which is a dihydroflavonoid found in citrus plants of the Rutaceae family and possesses the anti-nociceptive effect [81]] alleviated paclitaxel-induced mechanical and thermal hyperalgesia by reducing paclitaxel-mediated upregulation of P2X7 receptor, calcitonin gene-related peptide (CGRP) expression in DRG, and the infiltration of Iba-1⁺ macrophages into DRG [82]. When a water-based herbal decoction consisting of 28 medicinally important plants, Divya-Peedantak-Kwath (DPK), was given orally to mice treated with paclitaxel, paclitaxel-mediated heat/mechanical allodynia and hyperalgesia were reduced, by (i) decreasing oxidative stress factors (oxidized glutathione and malodialdehyde in sciatic nerves, (ii) reducing inflammatory cytokine (TNF-α) in serum, and (iii) reducing lymphocytic infiltration to sciatic nerves [25].

Besides these herbal medicines, an inhibitor for the dual leucine zipper kinase (DLK, a key mediator of axonal degeneration) also reversed cisplatin-induced mechanical allodynia [83]. In this study, RNA sequencing of DRGs obtained from mice treated with cisplatin revealed elevated monocyte-/macrophage-specific genes (Itgam and Treml2) and leukocyte cell surface marker genes (Il18rap, Clec5a, Cd33, selectin L, Il17rb, andIl34), and the increased expression of these genes was prevented with co-administration of the DLK inhibitor and cisplatin, suggesting that DLK inhibitor attenuates cisplatin-induced peripheral neuropathy by preventing immune cell infiltration into DRG [83]. Further, in a rat study, intravenous immunoglobulins (IVIg) significantly reduced both bortezomib-induced heat and mechanical allodynia by reducing CD68⁺ macrophage infiltration into the sciatic and caudal nerves [84].

These findings suggest that targeting neuroimmune interaction can be a potential preventive/therapeutic strategy for CIPN although further research in this area is clearly warranted (Table 1).

Table 1.

Potential Neuroimmune Targeted Treatments for CIPN

Therapeutic agent	Associated immune cells	CIPN behavior attenuated	CIPN-causing drug	Proposed mechanism of action	References
Apigenin	Microglia	Mechanical Heat	Paclitaxel	Downregulation of TNF-α and IL-1βa, reducing inflammation/oxidative stress. Activation of ARE signaling pathway.	Rezai-Zadeh, K., et al. 2008 Xie, W., et al. 2023
Dual leucine zipper kinase (DLK)	Macrophages Monocytes	Mechanical	Cisplatin	Upregulation of macrophage genes Itgam and Treml2. Activation of leukocyte marker genes.	Ma, J., et al. 2021
Divya-Peedantak-Kwath (DPK)	Macrophages Lymphocytes	Mechanical Heat	Paclitaxel	Reduction of inflammatory cytokines, oxidative stress factors, and infiltrating lymphocytes.	Balkrishna, A., et al. 2020
Intravenous Immunoglobulins (IVIg)	Macrophages	Mechanical Heat	Bortezomib	Recruitment of TNF-α and CD68+ positive macrophages.	Meregalli, C., et al. 2018
Syringaresinol	Microglia	Mechanical Cold	Oxaliplatin	Activation of spinal microglia, leading to upregulation of inflammatory mediator’s iNOS, p-ERK and p-NF- κB.	Bajpai, V.K., et al. 2018 Zhang, L., et al. 2021 Lee, J.H., et al. 2022
Trimethoxyflavanone	Macrophages	Mechanic al Heat	Paclitaxel	Reduction of upregulated P2X7 receptor Downregulation of calcitonin gene related peptide expression in DRG.	Mei, C., et al. 2023

5. Conclusions

While the cancer mortality rate has been dropping due to improvements in therapies available, such as adjuvant chemotherapies [85], many cancer patients treated with such cytotoxic agents still cope with long-term side effects, including CIPN. Not only does CIPN negatively affect their quality of life, but also their overall survival, since CIPN is the leading cause of treatment discontinuation or dose reduction. Therefore, patients with CIPN and their families pay a tremendous price physically, emotionally, and financially. From the health care system’s perspective, the financial burden of caring for these patients is growing steadily. To continue the reduction in cancer mortality and increase patients’ quality of life, revealing CIPN mechanisms and developing preventions/treatments for CIPN are desperately needed.

Unfortunately, currently available CIPN treatments have limited efficacy in preventing or controlling CIPN symptoms. As discussed in this review, the impacts of neuroimmune interaction on CIPN development have recently been appreciated (Figure 1). While most immune cells are involved in the development of CIPN through activation of inflammatory responses, T cells, interestingly, seem to be associated with the resolution of CIPN. Thus, further studies dissecting the differential roles of each immune cell are clearly justified. Moreover, because the mechanisms of cancer-killing effects differ between chemotherapeutic agents, pathophysiology of CIPN-related immune activation and immune cell recruitment into nerve tissues may also differ. Indeed, it had been demonstrated that oxaliplatin, cisplatin, and vincristine recruited different immune cells into DRGs [86]. Therefore, it is important to note that the mechanisms and preventions/treatments are hard to generalize and consequently should be chemotherapeutic agent dependent. Because each chemotherapy elicits a specific immune response, this makes it difficult to study CIPN. Furthermore, the impacts of underlying cancer on neuroimmune interactions should be considered when it comes to investigating not only the mechanisms of CIPN but also the development of preventive/therapeutic strategies for CIPN since cancer itself is known to impair immune systems [87]. Unfortunately, most preclinical studies to elucidate CIPN mechanisms and/or the therapeutic effects of several agents have been performed in tumor naïve animals. To increase the translational aspect of these preclinical studies, further studies in a tumor-bearing condition should be considered. Furthermore, age effects should not be overlooked. Indeed, incidence of CIPN in pediatric cancer patients has been reported to be between 3–13% [88], whereas that of adult CIPN patients has been reported to be between 4–70% [89]. Potential differences between pediatric and adult patients in CIPN incidence can be metabolic ability and neurobiological development of the peripheral nervous system. It has been posited that young children may metabolize vincristine quicker than older children or adult patients, resulting in reduction of CIPN by precluding vincristine plasma levels to reach toxic levels [90]. Moreover, DRG diameter, density, and myelination significantly changes from adolescence to adulthood. It has been suggested that these neurobiological changes could have an influence on risk and severity of CIPN [91]. Additionally, vincristine not only induces CIPN but also negatively affects motor neurons in pediatric patients [92], while adult patients develop predominantly sensory CIPN [93–95].

Figure 1. The mechanisms whereby immune cells contribute to the development of chemotherapy-induced peripheral neuropathy.

Dorsal root ganglia (DRG) sensory nerve fibers extend to the periphery of the body and are known to interact with immune cells. Both innate and adaptive immune responses following chemotherapeutic insults have been proposed to be involved in the development of chemotherapy-induced peripheral neuropathy (CIPN). Additionally, the chemotherapy-mediated activation or deactivation of the spinal immune cells has been thought to be a part of the mechanisms of CIPN development. The infiltration of monocytes/macrophages in nervous tissues plays crucial roles of CIPN development. Indeed, (i) the upregulation of monocyte chemoattractant protein-1 (MCP-1) expression in DRG following oxaliplatin treatment; (ii) the elevated levels of galectin-3 in Schwann cells within the sciatic nerve following paclitaxel treatment; and (iii) the enhanced vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells following vincristine treatment are responsible for the monocyte/macrophage infiltration, resulting in CIPN development. Specifically, after binding to endothelial cells, these infiltrating monocytes/macrophages are activated through the C-X3-C motif chemokine ligand 1 (CX3CL1) from endothelial cell/C-X3-C motif chemokine receptor 1 (CXCR1) on monocyte/macrophage axis and then produce reactive oxygen species (ROS). The resulting ROS then activate transient receptor potential ankyrin 1 (TRPA1) receptor on sciatic nerves, leading to increased vincristine-mediated peripheral neuropathy. In the skin environment, oxaliplatin and paclitaxel enhance tryptase and histamine release from mast cells, respectively. The mast cell-derived tryptase and histamine are also known to induce CIPN. In the spinal cord, (i) cisplatin increases triggering receptor expressed on myeloid cells 2 (TREM2), known to be involved in inflammatory cytokine production, in microglia; and (ii) oxaliplatin reduces the levels of insulin-like growth factor-1 (IGF1), known to maintain nerve survival, in astrocytes. Conversely, T cells have protective roles from CIPN. Paclitaxel-exposed T cells stimulate interleukin-10 (IL-10) production from macrophages through IL-13. Macrophage-derived IL-10 blocks the paclitaxel-induced peripheral neuropathy by binding to IL-10 receptor (IL-10R) on DRG. Graphics adapted from Smart Servier Medical Art (https://smart.servier.com/).

Despite these difficulties, current efforts in (i) elucidating how neuroimmune interactions augment development of a challenging clinical problem: CIPN and (ii) identifying neuroimmune interaction-targeting treatments for CIPN, discussed in this review are promising. Thus, further studies in this area are clearly worth pursuing. Once we better understand these mechanisms, the discoveries will lead to new strategies for reducing CIPN, so that patients with advanced cancer can continue their anti-cancer treatments and have better quality of life. While a better understanding of advanced cancer is necessary to improve patient overall survival, revealing the mechanisms of its complications will be equally vital to improving patient well-being.

Abbreviations:

ARE

Antioxidant Response Element

CCR2

C-C Motif Chemokine Receptor 2

CGRP

Calcitonin gene-related peptide

CI

Confidence Interval

CIPN

Chemotherapy-induced peripheral neuropathy

CXCR1

C-X3-C motif chemokine receptor 1

CX3CL1

C-X3-C motif chemokine ligand 1

DPK

Divya-Peedantak-Kwath

DRG

Dorsal root ganglion

DLK

Dual leucine zipper kinase

FDR

False discovery rate

GJE1

Gap junction protein epsilon 1

IBA-1

Ionized calcium-binding adapter molecule 1

ICAM-1

Intercellular adhesion molecule 1

IENF

Intraepidermal nerve fiber

IGF1

Insulin-like growth factor-1

IL-1βa

Interleukin 1β

IL-4

Interlukin-4

IL-6

Interlukin-6

IL-10

Interlukin-10

IL-13

interlukin-13

IL-20

Interlukin-20

iNOS

inducible nitric oxide synthase

IVIg

Intravenous immunoglobulins

MCP1 / MCP-1

Monocyte chemotactic protein 1

MMP9/2

matrix metalloproteinase 9

MTA

Microtubule-targeting agents

NRF2

Nuclear factor erythroid 2-related factor 2

p-ERK

Phosphorylated extracellular signal-regulated kinase

p-NF-κB

Phosphorylated nuclear factor-kappa B

PAR2

proteinase-activated receptor 2

PDE

phosphodiesterase

PKCε

protein kinase C epsilon isoform

ROS

Reactive oxygen species

RR

Risk ratio

SNP

single-nucleotide polymorphisms

TLR4

Toll-like receptor 4

TNF-α

Tumor-necrosis factor-alpha

TREM2

Triggering receptor expressed on myeloid cells 2

TRPA1

Transient receptor potential cation channels subfamily A member 1

TRPV1

Transient receptor potential cation channels subfamily V member 1

VCAM-1

Vincristine enhanced vascular cell adhesion molecule 1