RESUMO
Loss of the B2M gene is associated with tumour immune escape and resistance to immunotherapy. However, genetic alterations of the B2M gene are rare. We performed an integrative analysis of the mutational and transcriptional profiles of large cohorts of non-small-cell lung cancer (NSCLC) patients and found that epigenetic downregulation of B2M is common. B2M-low tumours exhibit a suppressive immune microenvironment characterized by reduced infiltration of immune cells of various lineages; in B2M-high tumours, more T and natural killer cells are present, but their activities are constrained by immune checkpoint molecules, indicating the diverse mechanisms of immune evasion. High levels of B2M mRNA, but not PD-L1, are correlated with an enhanced response to PD-1-based immunotherapy, suggesting its value for immunotherapy response prediction in solid tumours. Notably, a high tumour mutation burden (TMB) is associated with low B2M expression, which may explain the poor predictive value of the TMB in some situations. In syngeneic mouse models, genetic ablation of B2M in tumour cells causes resistance to PD-1-based immunotherapy, and B2M knockdown also diminishes the therapeutic efficacy. Moreover, forced expression of B2M in tumour models improves the response to immunotherapy, suggesting that B2M levels have significant impacts on treatment outcomes. Finally, we provide insight into the roles of transcription factors and KRAS mutations in B2M expression and the anticancer immune response. In conclusion, genetic and epigenetic regulation of B2M fundamentally shapes the NSCLC immune microenvironment and may determine the response to checkpoint blockade-based immunotherapy.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Microglobulina beta-2/genética , Animais , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: To assess the feasibility, safety, and preliminary effect of a 12-week multi-modal rehabilitation program targeted at improving health-related quality of life and physical activity levels of patients with lung cancer following treatment. METHODS: Patients with stage I to IIIA non-small cell lung cancer were included 6 to 12 weeks following completion of treatment. The intervention comprised of aerobic exercise (brisk walking), resistance training and 8-style Tai Chi. The 12-week program included 2 supervised center-based sessions per week of 90 minutes duration and home-based exercise. The primary outcomes were the feasibility and safety of the intervention. Secondary outcomes (assessed pre and post program) were physical and patient-reported outcomes. RESULTS: Seventy-eight patients were approached during the 6-month recruitment period and 17 (22%) consented to the study. Eight participants (47%) met the definition of adherence to the program (attending at least 70% of supervised sessions). No serious adverse events occurred. A significant reduction in anxiety and depression was observed post-program. In addition, improvements in respiratory function, sleep quality, and some health-related quality of life domains were observed post-program. There were no significant differences in functional capacity or physical activity levels. CONCLUSION: This multi-modal exercise training program was safe, although the feasibility of the program in its current state is not supported given the low consent rate and low adherence to the intervention.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Tai Chi Chuan , Exercício Físico , Terapia por Exercício , Estudos de Viabilidade , Humanos , Qualidade de VidaRESUMO
Metabolic alterations are well documented in various cancers. Non-small-cell lung cancers (NSCLCs) preferentially use lactate as the primary carbon source, but the underlying mechanisms are not well understood. We developed a lactate-dependent cell proliferation assay and found that dynamin-related protein (DRP1), which is highly expressed in KRAS-mutant NSCLC, is required for tumor cells to proliferate and uses lactate as fuel, demonstrating the critical role of DRP1 in the metabolic reprogramming of NSCLC. Metabolic and transcriptional profiling suggests that DRP1 orchestrates a supportive metabolic network to promote lactate utilization and redox homeostasis in lung cancer cells. DRP1 suppresses the production of reactive oxygen species (ROS) and protects cells against oxidative damage by enhancing lactate utilization. Moreover, targeting DRP1 not only reduces HSP90 expression but also enhances ROS-induced HSP90 cleavage, thus inhibiting activation of mitogen activated protein kinase and PI3K pathways and leading to suppressed lactate utilization and increased ROS-induced cell death. Taken together, these results suggest that DRP1 is a crucial regulator of lactate metabolism and redox homeostasis in KRAS-mutant lung cancer, and that targeting lactate utilization by modulating DRP1 activity might be an effective treatment for lung cancer.