The Role of Nerve Fibers in the Tumor Immune Microenvironment of Solid Tumors

Abstract

The concept of solid tumors innervation and tumor associated nerves is a recently emerging area of cancer research, with several studies showing strong evidence of its critical role in tumor biology. [3] Numerous studies in the field of cancer research and neuroscience have identified nerves as key promoters of different pathways of tumor growth and dissemination. In addition, it has been shown that nerves play immune regulatory functions and constitute an essential component of cellular microenvironments. [4] Furthermore, nerves seem to modulate many signaling pathways in tumor cells and other cellular elements of the TME. [5] The assessment of the presence, type, and density of nerve fibers performed in tumor tissue offers several opportunities to study nerve-related mechanisms implicated in tumor development. This is supported by studies revealing that differences of nerve fiber density in tumors, such as in pancreatic carcinoma, correlated patient's prognosis. [6] There are many techniques that can be used to evaluate nerve fibers in tissue, namely, routine hematoxylin and eosin (H&E) staining combined with micro scopy evaluation and more advanced technologies including artificial intelligence or hi-plex techniques that allow the analysis of several biomarkers in limited tissue samples. [7,8] More importantly, understanding the mutual interactions between nerves and solid tumors may accelerate the development of novel drugs and surgical therapeutic approaches. [9] Nerves seem to have a trophic and immune impact in tumors similarly to the well-known nerve functions in tissue regeneration, and in immunity, these features can potentially be exploited to develop novel and more efficacious therapeutic approaches. [10,11] These new therapeutic targets, alone or in combination with chemotherapy or immunotherapy could slow or stop cancer progression. [12] In this review we will briefly describe the historical background of the study of nerves in tumors, the mechanisms associated with this emergent concept of nerve fibers as important players in the TME including innervation of solid tumors, mechanisms of nerve fiber neogenesis, the complex interactions among nerve fibers and TME elements including immune cells, and its impact in tumor initiation and disease progression; we will also provide a summary of the approaches that can be used to assess tumor associated nerves in tissue;The importance of neurons and nerve fibers in the tumor microenvironment (TME) of solid tumors is now acknowledged after being unexplored for a long time; this is possible due to the development of new technologies that allow in situ characterization of the TME. Recent studies have shown that the density and types of nerves that innervate tumors can predict a patient's clinical outcome and drive several processes of tumor biology. Nowadays, several efforts in cancer research and neuroscience are taking place to elucidate the mechanisms that drive tumor-associated innervation and nerve-tumor and nerve-immune interaction. Assessment of neurons a...

Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment

“…Moreover, nerve–macrophage interactions also induce tumour metastasis by perineural invasion (PNI). PNI is defined as a pathologic process in which tumour metastasis is mediated by malignant cell-invaded nerves [ 153 ]. Schwann cells can secrete CCL2 to chemoattract CCR2-expressing monocytes to the PNI region, where they differentiate into macrophages to enhance nerve invasion in a cathepsin B-dependent manner [ 154 ].…”

Intratumoral Microbiome: Foe or Friend in Reshaping Tumor Microenvironment Landscape?

“…The tumor-infiltrating neurons can be sensory, adrenergic or cholinergic. Each of the aforementioned neuron types drive distinct disease outcomes, depending on the tumor type [45], while their existence in the TME promotes neural signaling through the production of neurotransmitters and neuropeptides and their cognate receptors on tumor cells, thus leading to tumor progression [45,46]. Another feature of the innervated microenvironment involves the perineural invasion, which is defined as the entry of tumor cells into the peripheral nerves, ultimately enabling the tumor dissemination to distant regions [44].…”

Recent Advances on Surface-Modified GBM Targeted Nanoparticles: Targeting Strategies and Surface Characterization

“…Unfortunately, it has been evidenced that tumors are often insensitive to antiangiogenic treatments with anti-VEGF therapies. This phenomenon has been mostly observed in highly innervated tumors, revealing the crucial role of tumor-associated nerves (TANs) in the efficacy of anticancer treatments [80,81]. Treating tumors with VEGF-targeted NPs could induce a response from TANs with production of neurosignals that might restore the angiogenic behavior of cancer cells, canceling the efficacy of the treatment [82].…”