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1.
Front Immunol ; 15: 1335387, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38433844

RESUMO

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.


Assuntos
Neoplasias , Neuropeptídeos , Animais , Camundongos , Humanos , Células Receptoras Sensoriais , Dor , Nociceptores , Microambiente Tumoral
2.
Nat Commun ; 12(1): 2936, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006861

RESUMO

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav1.8+ sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav1.8-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav1.8+ sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Dor Nociceptiva/imunologia , Células Receptoras Sensoriais/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Canal de Sódio Disparado por Voltagem NAV1.8/imunologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Infiltração de Neutrófilos/imunologia , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/virologia , Pele/imunologia , Pele/metabolismo , Pele/virologia
4.
Cancer Immunol Res ; 7(11): 1849-1863, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31527069

RESUMO

ß-Adrenergic receptor (ß-AR) signaling exerts protumoral effects by acting directly on tumor cells and angiogenesis. In addition, ß-AR expression on immune cells affects their ability to mount antitumor immune responses. However, how ß-AR signaling impinges antitumor immune responses is still unclear. Using a mouse model of vaccine-based immunotherapy, we showed that propranolol, a nonselective ß-blocker, strongly improved the efficacy of an antitumor STxBE7 vaccine by enhancing the frequency of CD8+ T lymphocytes infiltrating the tumor (TIL). However, propranolol had no effect on the reactivity of CD8+ TILs, a result further strengthened by ex vivo experiments showing that these cells were insensitive to adrenaline- or noradrenaline-induced AR signaling. In contrast, naïve CD8+ T-cell activation was strongly inhibited by ß-AR signaling, and the beneficial effect of propranolol mainly occurred during CD8+ T-cell priming in the tumor-draining lymph node. We also demonstrated that the differential sensitivity of naïve CD8+ T cells and CD8+ TILs to ß-AR signaling was linked to a strong downregulation of ß2-AR expression related to their activation status, since in vitro-activated CD8+ T cells behaved similarly to CD8+ TILs. These results revealed that ß-AR signaling suppresses the initial priming phase of antitumor CD8+ T-cell responses, providing a rationale to use clinically available ß-blockers in patients to improve cancer immunotherapies.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Vacinas Anticâncer/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/uso terapêutico , Células Cultivadas , Imunoterapia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Propranolol/farmacologia , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
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