Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer.

Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a mouse model for head and neck cancer and neuronal tracing, we show that tumor-infiltrating nerves connect to distinct brain areas. The activation of this neuronal circuitry altered behaviors (decreased nest-building, increased latency to eat a cookie, and reduced wheel running). Tumor-infiltrating nociceptor neurons exhibited heightened calcium activity and brain regions receiving these neural projections showed elevated Fos as well as increased calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment restored nesting and cookie test behaviors, it did not fully restore voluntary wheel running indicating that pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer.

A lot of cancer survivors experience a decline in mental health, persisting often decades after successful treatment. Many factors contribute to this reduced mental well-being, including the physical, emotional and financial stresses they experience. Scientists think that the increased prevalence of mental health disorders among cancer patients and survivors may also be linked to the cancer itself. Previous research has shown that most tumors, in particular in melanomas, cervical and ovarian cancers, and head and neck cancers, contain sensory nerves that sense thermal, mechanical and chemical changes and so alert an organism about a potential danger, such as extreme temperature, pressure, changes in pH or inflammation. To investigate whether these nerves contribute to the worsened mental health of cancer patients, Barr, Walz et al. studied male mice with tumors growing in their mouths, mimicking the disease of patients with head and neck cancers. The mice with tumors exhibited several altered behaviors linked to their well-being, suggesting that they had reduced overall health compared to mice without tumors. For example, they were less inclined to build nests, accept treats or run on a wheel. Next, Barr, Walz et al. injected a fluorescent dye into the tumors to label the nerves inside the cancerous growths. Fluorescence microscopy and imaging studies revealed that, days later, the dye had traveled to multiple regions of the brain, indicating that the nerves in the tumors had connected to a preexisting nerve circuit that included these brain regions. Further experiments revealed that the nerve cells in these brain regions were more active in mice with tumors and had different functional properties compared to mice without tumors. Removing the connecting nerves either genetically or with a drug improved all the behaviors of the mice with tumors. Treating the mice with painkillers also improved some but not all of their behaviors, indicating that pain is not the exclusive driver of such behavioral shifts. These two experiments suggest that the nerves from the tumors relay information about pain to the brain and contribute to reduced well-being of the mice. Further studies will test whether these tumor-brain connections also contribute to behavioral changes in mice with other types of cancer. The data suggest that disrupting the neural connections between a tumor and the brain may improve the mental health of patients with cancer, but more research is needed to establish this link.

Targeting the peripheral neural-tumour microenvironment for cancer therapy.

As the field of cancer neuroscience expands, the strategic targeting of interactions between neurons, cancer cells and other elements in the tumour microenvironment represents a potential paradigm shift in cancer treatment, comparable to the advent of our current understanding of tumour immunology. Cancer cells actively release growth factors that stimulate tumour neo-neurogenesis, and accumulating evidence indicates that tumour neo-innervation propels tumour progression, inhibits tumour-related pro-inflammatory cytokines, promotes neovascularization, facilitates metastasis and regulates immune exhaustion and evasion. In this Review, we give an up-to-date overview of the dynamics of the tumour microenvironment with an emphasis on tumour innervation by the peripheral nervous system, as well as current preclinical and clinical evidence of the benefits of targeting the nervous system in cancer, laying a scientific foundation for further clinical trials. Combining empirical data with a biomarker-driven approach to identify and hone neuronal targets implicated in cancer and its spread can pave the way for swift clinical integration.

Localized intratumoral delivery of immunomodulators for oral cancer and oral potentially malignant disorders.

Immunotherapy has developed into an important modality of modern cancer treatment. Unfortunately, checkpoint inhibitor immunotherapies are currently delivered systemically and require frequent administration, which can result in toxicity and severe, sometimes fatal, adverse events. Localized delivery of immunomodulators for oral cancer and oral potentially malignant disorders offers the promise of maximum therapeutic potential and reduced systemic adverse effects. This review will discuss the limitations of current standard-of-care systemic therapies and highlight research advances in localized, intratumoral delivery platforms for immunotherapy for oral cancer and oral potentially malignant disorders.

Cutaneous Squamous Cell Carcinoma of the Head and Neck: Pathological Features and What They Mean for Prognosis and Treatment.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers worldwide, with an incidence that has increased over the past 30 years. Although usually curable with excision, cSCC can become widely metastatic and aggressive with poor outcomes. Whereas the clinical and radiographic extent of any cancer will always guide selection of treatment modality, pathological features of cSCC also play an important role in determining prognosis and, subsequently, the need for further therapy. Therefore, reviewing and summarizing the current literature regarding pathological prognostic indicators of cSCC is essential to improving clinical outcomes. The present literature review yielded depth of invasion, surgical margins, perineural invasion, extranodal extension, lymphovascular invasion, tumor grade, tumor subtype, premalignant lesions, and molecular markers as key prognostic indicators, all with varying recommendations for adjuvant therapy. Notably, some of these factors have not been incorporated into either the American Joint Committee on Cancer staging system (8th edition) or National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for cSCC. This review highlights a need for further research into these prognostic indicators and their role in determining the need for adjuvant treatment in head and neck cSCC.

Neural landscape is associated with functional outcomes in irradiated patients with oropharyngeal squamous cell carcinoma.

The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.

Oral Pre-malignancy: An Update on Novel Therapeutic Approaches.

PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of the current advances in managing and preventing progression of oral potentially malignant disorders (OPMDs), focusing on their histological and clinicopathological features, and management. RECENT FINDINGS: Recent studies, including a multicenter cross-sectional study, have identified oral leukoplakia as the most prevalent form of OPMD, comprising over half of the cases examined. Advances in histological grading, specifically the World Health Organization's three-tier system (mild, moderate, and severe dysplasia), have significantly enhanced the accuracy of risk assessment for malignant transformation. Additionally, treatments such as surgical interventions, photodynamic therapy, and chemopreventive and molecularly targeted agents are being evaluated for their safety and efficacy as well as, immune checkpoint inhibitors being evaluated as potential preventive strategies to halt the progression of OPMDs. The management of OPMDs remains challenging due to the lack of standardized screening protocols and varied clinical management approaches. Despite this, recent advancements in diagnostic grading and therapeutic interventions provide a framework for improved treatment outcomes. Continued research into the molecular and cellular mechanisms driving development and progression of OPMDs and innovative treatment trials are essential to optimize strategies that prevent malignant progression and thereby reduce the global health burden of oral cancer.

Targeting sinonasal undifferentiated carcinoma with a combinatory immunotherapy approach.

PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME). EXPERIMENTAL DESIGN: Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed. RESULTS: Anti-PD-L1 blockade enhanced NK cell lysis of SNUC cell lines ∼5.4 fold (P ≤ 0.0001). This effect was blocked by a CD16 neutralizing antibody demonstrating activity through an antibody-dependent cellular cytotoxicity (ADCC) mediated pathway. ADCC-dependent lysis of SNUC cells was further enhanced by upregulation of PD-L1 on tumor cells by exogenous interferon-gamma (IFN-γ) administration or interleukin-15 (IL-15) stimulated IFN-γ release from NK cells. Combination treatment with anti-PD-L1 blockade and IL-15 superagonism enhanced NK-cell killing of SNUC cells 9.6-fold (P ≤ 0.0001). Untreated SNUC patient tumor samples were found to have an NK cell infiltrate and PD-L1+ tumor cells at a median of 5.4 cells per mm2. A striking 55.7-fold increase in CKlow tumor cell/NK cell interactions was observed in patients without disease recurrence after treatment (P = 0.022). Patients with higher CD3+CD8+ in the stroma had a significantly improved 5-year overall survival (P = 0.0029) and a significant increase in CKlow tumor cell/CD8+ cytotoxic T cell interactions was noted in long-term survivors (P = 0.0225). CONCLUSION: These data provide the pre-clinical rationale for ongoing investigation into combinatory immunotherapy approaches for SNUC.

Next Directions in the Neuroscience of Cancers Arising outside the CNS.

SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.

The Feasibility and Outcome of Integra® Bilayer Matrix in the Reconstruction of Oral Cavity Defects.

OBJECTIVE: To evaluate the feasibility, safety, and failure rate of Integra® Bilayer Wound Matrix (Integra) in the reconstruction of oral cavity defects. STUDY DESIGN: Retrospective cohort study. SETTING: All study information was collected from a single academic tertiary care hospital. METHODS: Subjects included adult patients who underwent oral cavity resection and immediate subsequent reconstruction with Integra® Bilayer Wound Matrix at MD Anderson Cancer Center between the years 2015 and 2020. The following variables were collected: patient's demographics, comorbidities, disease stage, treatment and reconstruction modalities, and surgical outcome from the medical records. Statistical analysis included distribution analysis for all collected parameters and Pearson's χ2 tests to find correlation between variables and take rate of Integra. RESULTS: Eighty-three patients underwent reconstruction with Integra® Bilayer Wound Matrix dressing. Average age was 66 years old. Thirty-nine patients (47%) had history of previous resections for oral cavity tumors. Fourteen patients (17%) had history of radiation therapy to the Head and Neck region. Most common pathology was invasive squamous cell carcinoma (75%) followed by dysplasia (12%). Complete wound healing with good cellular integration occurred in 83 patients (96%) with only 3 failures requiring additional surgery. Reconstruction of mandibulectomy defects was associated with increased risk of dehiscence and bone exposure (0.66, P = .03). CONCLUSION: This study shows promising results with high take rate of Integra® Bilayer Wound Matrix dressing in the reconstruction of various oral cavity defects. We encourage surgeons to adopt this technique as a viable and versatile option into the reconstruction ladder of oral cavity defects.

Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer.

Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a male mouse model for head and neck cancer, we utilized neuronal tracing techniques and show that tumor-infiltrating nerves indeed connect to distinct brain areas via the ipsilateral trigeminal ganglion. The activation of this neuronal circuitry led to behavioral alterations represented by decreased nest-building, increased latency to eat a cookie, and reduced wheel running. Tumor-infiltrating nociceptor neurons exhibited heightened activity, as indicated by increased calcium mobilization. Correspondingly, the specific brain regions receiving these neural projections showed elevated cFos and delta FosB expression in tumor-bearing mice, alongside markedly intensified calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons in tumor-bearing mice led to decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment successfully restored behaviors involving oral movements to normalcy in tumor-bearing mice, it did not have a similar therapeutic effect on voluntary wheel running. This discrepancy points towards an intricate relationship, where pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer. Significance Statement: Head and neck cancers are infiltrated by sensory nerves which connect to a pre-existing circuit that includes areas in the brain. Neurons within this circuit are altered and mediate modifications in behavior.

Repurposing EGFR Inhibitors for Oral Cancer Pain and Opioid Tolerance.

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.

Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by interleukin-6 blockade.

While the nervous system has reciprocal interactions with both cancer and the immune system, little is known about the potential role of tumor associated nerves (TANs) in modulating anti-tumoral immunity. Moreover, while peri-neural invasion is a well establish poor prognostic factor across cancer types, the mechanisms driving this clinical effect remain unknown. Here, we provide clinical and mechniastic association between TANs damage and resistance to anti-PD-1 therapy. Using electron microscopy, electrical conduction studies, and tumor samples of cutaneous squamous cell carcinoma (cSCC) patients, we showed that cancer cells can destroy myelin sheath and induce TANs degeneration. Multi-omics and spatial analyses of tumor samples from cSCC patients who underwent neoadjuvant anti-PD-1 therapy demonstrated that anti-PD-1 non-responders had higher rates of peri-neural invasion, TANs damage and degeneration compared to responders, both at baseline and following neoadjuvant treatment. Tumors from non-responders were also characterized by a sustained signaling of interferon type I (IFN-I) - known to both propagate nerve degeneration and to dampen anti-tumoral immunity. Peri-neural niches of non-responders were characterized by higher immune activity compared to responders, including immune-suppressive activity of M2 macrophages, and T regulatory cells. This tumor promoting inflammation expanded to the rest of the tumor microenvironment in non-responders. Anti-PD-1 efficacy was dampened by inducing nerve damage prior to treatment administration in a murine model. In contrast, anti-PD-1 efficacy was enhanced by denervation and by interleukin-6 blockade. These findings suggested a potential novel anti-PD-1 resistance drived by TANs damage and inflammation. This resistance mechanism is targetable and may have therapeutic implications in other neurotropic cancers with poor response to anti-PD-1 therapy such as pancreatic, prostate, and breast cancers.

Targeting the Nerve-Cancer Circuit.

The tumor microenvironment is innervated by sensory, sympathetic, and parasympathetic nerves that actively stimulate cancer growth and dissemination. The cross-talk among the peripheral nerves, cancer cells, and stromal cells is mediated by a diverse set of bioactive ligands and their corresponding receptors. Dissecting the specific neuronal subtypes and molecular signals that drive cancer-nerve interaction holds the hope of developing targeted therapies for cancer. A recent study by Restaino and colleagues demonstrated that regardless of tumor type, origin, or anatomic location, tumors are densely innervated, predominantly by transient receptor potential cation channel subfamily V member 1 positive (TRPV1+) sensory fibers. The intratumoral fibers likely have functional connectivity and contribute to increased electrical activity in the tumor bed. Importantly, the neuropeptide substance P produced by intratumoral fibers stimulates its neurokinin 1 receptor (NK1R) expressed on tumor cells to drive tumor proliferation and migration. The findings raised the intriguing possibility of a generalizable molecular pathway that mediates cancer-nerve interaction that can be targeted to inhibit tumor growth and metastasis across different tumor types.

Beta-Blocker Use Is Associated With Worse Relapse-Free Survival in Patients With Head and Neck Cancer.

PURPOSE: Although beta-blockers (BBs) have been hypothesized to exert a beneficial effect on cancer survival through inhibition of beta-adrenergic signaling pathways, clinical data on this issue have been inconsistent. We investigated the impact of BBs on survival outcomes and efficacy of immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC), non-small-cell lung cancer (NSCLC), melanoma, or squamous cell carcinoma of the skin (skin SCC), independent of comorbidity status or cancer treatment regimen. METHODS: Patients (N = 4,192) younger than 65 years with HNSCC, NSCLC, melanoma, or skin SCC treated at MD Anderson Cancer Center from 2010 to 2021 were included. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were calculated. Kaplan-Meier and multivariate analyses adjusting for age, sex, TNM staging, comorbidities, and treatment modalities were performed to assess the effect of BBs on survival outcomes. RESULTS: In patients with HNSCC (n = 682), BB use was associated with worse OS and DFS (OS: adjusted hazard ratio [aHR], 1.67; 95% CI, 1.06 to 2.62; P = .027; DFS: aHR, 1.67; 95% CI, 1.06 to 2.63; P = .027), with DSS trending to significance (DSS: aHR, 1.52; 95% CI, 0.96 to 2.41; P = .072). Negative effects of BBs were not observed in the patients with NSCLC (n = 2,037), melanoma (n = 1,331), or skin SCC (n = 123). Furthermore, decreased response to cancer treatment was observed in patients with HNSCC with BB use (aHR, 2.47; 95% CI, 1.14 to 5.38; P = .022). CONCLUSION: The effect of BBs on cancer survival outcomes is heterogeneous and varies according to cancer type and immunotherapy status. In this study, BB intake was associated with worse DSS and DFS in patients with head and neck cancer not treated with immunotherapy, but not in patients with NSCLC or skin cancer.

Non-Melanoma Skin Cancer Detection in the Age of Advanced Technology: A Review.

Skin cancer is the most common cancer diagnosis in the United States, with approximately one in five Americans expected to be diagnosed within their lifetime. Non-melanoma skin cancer is the most prevalent type of skin cancer, and as cases rise globally, physicians need reliable tools for early detection. Artificial intelligence has gained substantial interest as a decision support tool in medicine, particularly in image analysis, where deep learning has proven to be an effective tool. Because specialties such as dermatology rely primarily on visual diagnoses, deep learning could have many diagnostic applications, including the diagnosis of skin cancer. Furthermore, with the advancement of mobile smartphones and their increasingly powerful cameras, deep learning technology could also be utilized in remote skin cancer screening applications. Ultimately, the available data for the detection and diagnosis of skin cancer using deep learning technology are promising, revealing sensitivity and specificity that are not inferior to those of trained dermatologists. Work is still needed to increase the clinical use of AI-based tools, but based on the current data and the attitudes of patients and physicians, deep learning technology could be used effectively as a clinical decision-making tool in collaboration with physicians to improve diagnostic efficiency and accuracy.

Predictors of postoperative performance status after surgical management of infratemporal fossa malignancies.

Infratemporal fossa (ITF) tumors are difficult to access surgically due to anatomical constraints. Moreover, aggressive ITF carcinomas and sarcomas necessitate aggressive treatment strategies that, along with tumor-related symptoms, contribute to decreases in patient performance status. To assess factors that predict postoperative performance in patients undergoing surgery for ITF tumors. We reviewed medical records for all patients surgically treated for an ITF malignancy between January 1, 1999, and December 31, 2017, at our institution. We collected patient demographics, preoperative performance, tumor stage, tumor characteristics, treatment modalities, pathological data, and postoperative performance data. The 5-year survival rate was 62.2%. Higher preoperative Karnofsky Performance Status (KPS) score (n = 64; p < 0.001), short length of stay (p = 0.002), prior surgery at site (n = 61; p = 0.0164), and diagnosis of sarcoma (n = 62; p = 0.0398) were predictors of higher postoperative KPS scores. Percutaneous endoscopic gastrostomy (PEG) (n = 9; p = 0.0327), and tracheostomy tube placement (n = 20; p = 0.0436) were predictors of lower postoperative KPS scores, whereas age at presentation (p = 0.72), intracranial tumor spread (p = 0.8197), and perineural invasion (n = 40; p = 0.2195) were not. Male patients and patients with carcinomas showed the greatest decreases in KPS scores between pretreatment and posttreatment. Higher preoperative KPS score and short length of stay were the best predictors of higher postoperative KPS scores. This work provides treatment teams and patients with better information on outcomes for shared decision-making.

Review of the Tumor Microenvironment in Basal and Squamous Cell Carcinoma.

It is widely known that tumor cells of basal and squamous cell carcinoma interact with the cellular and acellular components of the tumor microenvironment to promote tumor growth and progression. While this environment differs for basal and squamous cell carcinoma, the cellular players within both create an immunosuppressed environment by downregulating effector CD4+ and CD8+ T cells and promoting the release of pro-oncogenic Th2 cytokines. Understanding the crosstalk that occurs within the tumor microenvironment has led to the development of immunotherapeutic agents, including vismodegib and cemiplimab to treat BCC and SCC, respectively. However, further investigation of the TME will provide the opportunity to discover novel treatment options.

Neuro-immune interactions and immuno-oncology.

The nervous system is an important component of the tumor microenvironment (TME), driving tumorigenesis and tumor progression. Neuronal cues (e.g., neurotransmitters and neuropeptides) in the TME cause phenotypic changes in immune cells, such as increased exhaustion and inhibition of effector cells, which promote immune evasion and cancer progression. Two types of immune regulation by tumor-associated nerves are discussed in this review: regulation via neuronal stimuli (i.e., by neural transmission) and checkpoint-mediated neuronal immune regulation. The latter occurs via the expression of immune checkpoints on the membranes of intratumoral nerves and glial cells. Here, we summarize novel findings regarding the neuroimmune circuits in the tumor milieu, while emphasizing the potential targets of new and affordable anticancer therapeutic approaches.

Immune checkpoint therapy-current perspectives and future directions.

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.