From pain to tumor immunity: influence of peripheral sensory neurons in cancer

Abstract

The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated anti-tumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it.

Keywords: cancer; immune cells; neuropeptides; nociceptors; pain; peripheral sensory neurons; tumor immunity; tumor microenvironment.

Figure 1

Pain circuit and its triggers in cancer. The cancer pain circuit comprises four levels of regulation. The initial level (I, axon sensitization) involves the sensitization of nerve endings of peripheral sensory neurons (PSNs) within the tumor microenvironment (TME), conveying neuronal information to sensory ganglia (DRG, VG, and TG) for integration (II, sensory ganglia integration). Next, PSNs from DRG afferent project nerve endings into the dorsal horn of the spinal cord, while PSNs from TG and VG project directly into the brainstem. In spinal cord and brainstem, neuropeptides (mainly SP, CGRP, and somatostatin) and glutamate from primary afferent fibers, along with other neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine produced by second-order nociceptive neurons and interneurons, exert their effects on spinal and supraspinal neurons (III, central sensitization). Finally, spinal and supraspinal projection neurons relay this information to higher brain regions including the brainstem, somatosensory, insular, cingulate and prefrontal cortices, and thalamus and subcortical areas, where their integration can lead to pain perception (IV, cognitive perception). Cancer pain primarily arises from two main sources: “nociceptive triggers” and “neuropathic triggers”. Nociceptive stimuli encompass algogenic mediators released by the TME and nerve sprouting. Neuropathic triggers, on the other hand, are a consequence of nerve damage caused by tumor cell invasion (perineural invasion), immune cell invasion (neuritis), nerve compression, and the effects of radiotherapy and chemotherapy. DRG, dorsal root ganglia; VG, vagal ganglia; TG, trigeminal ganglia. Created with BioRender.com.

Figure 2

Algogenic factors in the tumor microenvironment. The tumor microenvironment (TME) generates numerous algogenic factors that are capable of sensitizing the peripheral sensory neurons (PSNs) innervating the tumor. This sensitization initiates a signaling cascade in the PSN, leading to sensations of pain or hyperalgesia, and also triggers the release of neuropeptides such as CGRP and SP. Some of these factors are associated to inflammation within the tumor, such as cytokines and chemokines, while other molecular factors are directly linked to tumor cells, such as exosomes. Inflammation and hypoxic conditions also promote tumor cell necrosis, leading to the production of damage-associated molecular patterns (DAMPs). Additionally, several other mediators, such as neurotrophic factors, neuromediators, and angiogenesis-related molecules, possess algogenic properties. On the contrary, certain molecule like PD-L1 can inhibit the activity of PSNs by limiting the activation of TRPV1. ASIC, acid-sensing ion channel; ATP, adenosine triphosphate; BDKRB1/2, bradykinin receptor B1/2; BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CGRP, calcitonin gene-related peptide; CCL-2, C–C motif chemokine 2; CCR2, C–C chemokine receptor type 2; EP1–4, prostaglandin E2 receptor 1-4; ETA-R, endothelin receptor type A; ETB-R, endothelin receptor type B; ET-1, endothelin 1; G-CSF, granulocyte colony-stimulating factor; G-SCFR, granulocyte colony-stimulating factor receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; Gp130, glycoprotein 130; IL, interleukin; NGF, nerve growth factor; PAR2, proteinase-activated receptor 2; PD-1, programmed death 1; PD-L1, programmed death-ligand 1; PGE2, prostaglandin E2; P2X2/3, purinergic receptor P2X2/3; SLPI, secretory leukocyte protease inhibitor; SP, substance P; TNFα, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; Trk, tropomyosin receptor kinase; TRPV1, transient receptor potential cation channel subfamily V member 1; VEGF, vascular endothelial growth factor; VEGFR1, vascular endothelial growth factor receptor 1. Created with BioRender.com.

Figure 3

Crosstalk between pain and stress response in cancer. Sensitization of peripheral sensory neurons (PSNs) within the tumor microenvironment (TME) leads to the localized release of neuropeptides. Additionally, these neurons transmit an afferent nerve influx to the spinal cord, which relays this information to the brain. The cognitive processing of this information in the brain is responsible for pain perception (background). In the meantime, in response to the psychological stress caused by the disease, the brain activates the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic neurons, resulting in the release of stress hormones [(nor-)adrenaline and glucocorticoids] into the TME (blue background). Interactions between the sensory axis and the sympathetic/HPA axis can take place at several levels: (1) at the brain level, afferent nerve impulses can trigger a stress response, resulting in activation of the HPA axis and the sympathetic system (solid red arrow). Similarly, it is possible that the stress induced by the disease may enhance pain perception (blue dotted arrow). (2) At the spinal cord and dorsal root ganglia (DRG) level, PSNs can transmit nerve impulses to interneurons that directly activate sympathetic neurons (solid red arrow). Additionally, due to nerve injury, sympathetic neurons from sympathetic ganglia (SG) may extend into DRG to activate PSNs. (3) Within the tumor itself, stress hormones may sensitize PSNs (solid blue arrow). All of these interactions result in the differential integration of pain and stress, and they influence tumor growth and the associated anti-tumor immune response. Created with BioRender.com.

Figure 4

Influence of peripheral sensory neurons on tumor growth and antitumor immune response. The impact of peripheral sensory neurons (PSNs) on cancer development has primarily been investigated in murine models of melanoma, oral squamous carcinoma, pancreatic cancer, and breast cancer/metastasis. In these models, PSNs expressing Nav1.8 and TRPV1 ion channels release the neuropeptides CGRP and SP into the tumor microenvironment (TME). This leads to either pro-tumoral effects (indicated by the red background at the top) or anti-tumoral effects (indicated by the green background at the bottom) on primary tumors or metastases, depending on the specific cancer models studied. The results obtained for each tumor/model are represented in separate quadrants, delineated by dashed lines. Specifically, PSNs promote the growth of primary tumors in oral carcinoma models and inhibit the ability of mammary tumors to metastasize. Their influence on melanoma and pancreatic cancer is mixed and can depend on factors such as the location of melanoma tumor cell injection (pro-tumoral when injected in dermis and anti-tumoral when injected subcutaneously) and the genetic models of pancreatic cancer used (pro-tumoral in spontaneous development models and anti-tumoral in an inflammatory inducible model). Furthermore, PSNs also influence the anti-tumor immune response, affecting factors such as leukocyte recruitment, cytokine production, and the expression of exhaustion markers on T cells (as indicated in the yellow box). CGRP, calcitonin gene-related peptide; CTLA-4, cytotoxic T-lymphocyte antigen-4; DC, dendritic cell; IFN, interferon; NK, natural killer lymphocyte; PD1, programmed cell death protein 1; SP, substance P; Tim3, T-cell immunoglobulin and mucin containing protein-3; Treg, regulatory T cell; TRPV1, transient receptor potential cation channel subfamily V member 1. Created with BioRender.com.