Sensory neurons innervate the tumor microenvironment (TME) and are active contributors to tumor progression and immune evasion. Across multiple cancer types, higher intratumoral nerve density is associated with worse clinical outcomes, including increased lymph node metastasis, local recurrence, and reduced survival. This relationship is driven, at least in part, by local immunosuppression arising from neuropeptide and neurotransmitter paracrine signaling within the TME. Nociceptive sensory neurotransmission impacts tumor-infiltrating immune cells to promote T-cell exhaustion, mast cell degranulation, and stromal remodeling, collectively constructing a barrier to effective antitumor immunity. Beyond paracrine signaling, sensory neurons themselves express immune checkpoint proteins, including programmed cell death ligand-1, providing an additional mechanism by which the sensory nervous system participates in local immune regulation. Preclinical studies have established that targeting sensory neuron signaling, whether through denervation, neuropeptide antagonism, or axon guidance inhibition, can relieve TME immunosuppression and improve the efficacy of immune-based therapies. Several Food and Drug Administration (FDA)-approved agents developed for non-oncologic indications, including calcitonin gene-related peptide receptor antagonists approved for migraine, and the NK-1R antagonist Aprepitant, represent immediately available candidates for repurposing in combination immunotherapy strategies. The relationship between sensory neurons and immunotherapy is bidirectional; however, immunotherapies also act on sensory neurons, and this interaction likely contributes to the development and severity of immune-related adverse events through disruption of constitutive neuronal checkpoint signaling and neurogenic amplification of tissue inflammation. Sensory neurons in densely innervated barrier organs may serve as neuroimmune amplifiers that worsen the severity of colitis, pneumonitis, and dermatitis during checkpoint blockade. This review examines the evidence for how sensory neural signaling shapes immunotherapy efficacy, and how immunotherapies impinge on sensory neuron biology to promote adverse events. Throughout, we highlight translational opportunities where modulation of the sensory nervous system may improve therapeutic outcomes or reduce treatment toxicity.
Background Therapeutic options for clear cell renal cell carcinoma (ccRCC) are limited. Recent clinical trials showed the efficacy of chimeric antigen receptor (CAR)-T cell therapy in treating ccRCC. However, heterogeneous expression of targeting antigen drives immune escape and impairs therapeutic efficacy. Bispecific CARs co-targeting two tumor-associated antigens may overcome this limitation.Methods Human leucocyte antigen-G (HLA-G) and CD70 expression in normal and cancer tissues were analyzed using public RNA sequencing databases and immunohistochemistry of patient samples. An HLA-G CAR was engineered using its natural receptor human inhibitory receptors Ig-like transcript 4 (ILT4). The binding affinity of ILT4 to HLA-G was improved through structure-based rational design. A CD70 nanobody sequence was then incorporated into the HLA-G CAR to generate an HLA-G/CD70 bispecific CAR, together with a CD70-targeting short hairpin RNA (shRNA) to prevent CAR-T cell fratricide. A panel of linkers between the two antigen-binding domains was compared with optimize the CAR signal, and lead candidates were evaluated in vitro and in vivo using heterogeneous tumor models.Results HLA-G and CD70 were identified as ideal bispecific CAR-T targets to overcome the heterogeneity of ccRCC. An ILT4 mutant (Mut-5) with enhanced binding affinity to HLA-G was obtained. The HLA-G CAR derived from this high-affinity ILT4 mutant elicited enhanced antigen-specific cytotoxicity. An HLA-G/CD70 bispecific CAR was subsequently developed by connecting the affinity-optimized ILT4 mutant and a CD70 nanobody via an optimized (G4S)2 linker. To avoid fratricide of the bispecific CAR-T cells mediated by the expression of CD70, we incorporated a CD70 shRNA into the vector. The bispecific CAR showed specific cytotoxicity against both antigens, respectively, and mediated high antitumor activity toward double-positive tumor cells. Bispecific CAR-T cells effectively suppressed heterogeneous tumor growth in vivo and displayed less exhaustion compared with single-target CAR-T cells.Conclusions We established an affinity-optimized HLA-G/CD70 bispecific CAR as a promising strategy to overcome antigen heterogeneity-mediated resistance and immune escape in ccRCC.
Background Different metastatic sites in advanced melanoma show distinct responses to immune checkpoint inhibitors (ICIs). In patients treated with ICI, liver metastases are associated with reduced responses, while lung metastases are associated with improved responses. Metabolic reprogramming, including enhanced glycolysis and hypoxia-associated signaling, is a hallmark of tumor progression. Increased hypoxia-inducible factor 1 (HIF1α) expression has been associated with poorer prognosis and reduced response to ICI across several solid malignancies. We characterized and compared metabolic and hypoxic profiles across melanoma metastatic sites to provide insight into organ-specific responses to ICI.Methods We described metabolic and hypoxic profiles in tumor samples from 182 melanoma patients across metastatic sites, including liver (n=24), lung (n=35), brain (n=41), lymph node (n=25), and subcutaneous tissue (n=57). Multiplex immunohistochemistry staining (n=92; CD3, SOX10, CAIX, HIF1α, GLUT1) and transcriptomic analysis of bulk RNA sequencing (n=158), were performed to compare cell densities and gene expression across these sites.Results Liver metastases showed upregulation of glycolytic and metabolic pathways compared with other sites, though 97% of pathways were also characteristic of normal liver tissue; SLC2A1 (GLUT1), however, was selectively elevated in liver metastases relative to normal liver, consistent with tumor-specific metabolic reprogramming overlayed on the hepatic niche. Liver, lung, and brain metastases exhibited higher proportions of GLUT1+CD3+ T cells compared with lymph node and subcutaneous metastases. In both liver and lung, GLUT1+ tumor regions had lower T cell infiltration than GLUT1- regions. Lung metastases had the highest HIF1α expression, while liver showed reduced expression of CAIX compared with other sites.Conclusions These results demonstrate that the metabolic features of melanoma metastases and their accompanying immune cells differ across anatomical sites, possibly reflecting both the intrinsic biology of the host organ as well as tumor-specific metabolic reprogramming. This variability may contribute to organ-specific differences in response to ICI. They highlight the potential for therapies targeting metabolic pathways to overcome liver-mediated ICI resistance.
Background Diet rich in fat, such as high-fat diet (HFD) and ketogenic diet (KD), has complex impacts on immunity. Neutrophils adapt to tissue-specific signals and exert innate defense functions against infections and malignancies. However, whether and how dietary fat shapes tissue-specific neutrophil functions remains unclear. This study aims at determining the effect of dietary fat on tissue-specific pulmonary antitumor responses mediated by neutrophils.Methods Mouse models of HFD or KD feeding, in combination with a lung metastatic B16 melanoma or a primary Lewis lung carcinoma lung cancer model, were used to determine the impact of dietary fat on pulmonary tissue-specific reprogramming of antitumor functions in neutrophils. A multitude of experimental approaches were used to address the mechanisms through which HFD/KD boosts antitumor functions of intrapulmonary neutrophils. We also performed correlation analysis between immune activation signatures in human lung cancer-infiltrating neutrophils and serum lipids, and analyzed published single-cell transcription data in human lungs, to determine the potential correlation between serum lipid contents or endothelial cell-derived signals and antitumor functions of lung neutrophils.Results Both HFD-fed and KD-fed mice demonstrated enhanced neutrophil-mediated pulmonary tumor resistance compared with chow diet-fed mice, in either a prophylactic or a therapeutic setting. Intrapulmonary, but not systemic, neutrophils in HFD/KD-fed mice exhibited enhanced potential for reactive oxygen species (ROS) production and ROS-dependent tumor cytotoxicity. Mechanistically, HFD/KD-induced increased serum palmitic acid (PA) and cholesterol stimulate lung vascular endothelial cells (LVECs), which reprogram neutrophils via contact-dependent and intercellular adhesion molecule-1-dependent mechanisms. In humans, increased serum cholesterol levels are associated with increased myeloperoxidase contents in lung cancer-infiltrating neutrophils, and intensified adhesion and priming signals from human LVECs are potentially associated with immune activation in intrapulmonary neutrophils.Conclusions These data suggest that dietary fat boosts lung tissue-specific antitumor immunity mediated by neutrophils with an enhanced potential for ROS production, which are primed by LVECs stimulated by elevated serum PA and cholesterol. Our findings highlight the roles of dietary fats in shaping neutrophil functions in a tissue-specific manner. Dietary intervention targeting tissue-specific reprogramming of neutrophils, therefore, represents a potential strategy against malignancies in the lungs.
Background Small cell lung cancer (SCLC) has a poor prognosis despite standard first-line chemoimmunotherapy. Reliable, non-invasive biomarkers for risk stratification are urgently needed. Three-dimensional (3D) body composition (BC) analysis from chest CT scans offers a promising approach to assess systemic metabolic status.Methods In this multicenter study, we analyzed patients treated with first-line chemoimmunotherapy across five institutions. Using a deep learning model, 3D BC parameters were automatically extracted from baseline chest CTs. We evaluated their associations with overall survival (OS) and progression-free survival using Kaplan-Meier and Cox regression analyses. A total of 101 machine learning model configurations were evaluated to develop predictive models, and the SHapley Additive exPlanations method was applied to enhance model interpretability. Additionally, we investigated the association between BC parameters and CD8+ T-cell infiltration in the tumor microenvironment.Results Among 575 patients (training: 161; internal validation: 69; external validation: 345), all four 3D BC indices significantly stratified OS. Multivariable Cox analysis showed that higher skeletal muscle volume index was independently associated with better OS (HR=0.956, 95% CI 0.928 to 0.985, p=0.003), whereas higher visceral fat volume index was associated with worse OS (HR=1.017, 95% CI 1.002 to 1.032, p=0.026). 3D BC provided more pronounced prognostic stratification than conventional two-dimensional measures and body mass index. The selected linear discriminant analysis model achieved area under the curves of 0.756, 0.781, and 0.783 in the training, internal validation, and external validation cohorts, respectively. In an exploratory subset of 35 patients, higher skeletal muscle volume index was associated with increased intratumoral CD8+T cell density.Conclusions Higher skeletal muscle volume index was associated with better OS, whereas higher visceral fat volume index was associated with worse OS. Automated 3D BC may provide complementary non-invasive prognostic information in patients with SCLC receiving first-line chemoimmunotherapy.
