Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently ...required. Here, we show that the frequency of PD-1
CD8
T cells relative to that of PD-1
regulatory T (T
) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8
T cells and T
cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1
CD8
T cells and enhanced PD-1
T
cell-mediated immunosuppression. A profound reactivation of effector PD-1
CD8
T cells rather than PD-1
T
cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Oncogenic epidermal growth factor receptor (EGFR) signaling plays an important role in regulating global metabolic pathways, including aerobic glycolysis, the pentose phosphate pathway (PPP), and ...pyrimidine biosynthesis. However, the molecular mechanism by which EGFR signaling regulates cancer cell metabolism is still unclear. To elucidate how EGFR signaling is linked to metabolic activity, we investigated the involvement of the RAS/MEK/ERK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways on metabolic alteration in lung adenocarcinoma (LAD) cell lines with activating EGFR mutations. Although MEK inhibition did not alter lactate production and the extracellular acidification rate, PI3K/mTOR inhibitors significantly suppressed glycolysis in EGFR-mutant LAD cells. Moreover, a comprehensive metabolomics analysis revealed that the levels of glucose 6-phosphate and 6-phosphogluconate as early metabolites in glycolysis and PPP were decreased after inhibition of the PI3K/AKT/mTOR pathway, suggesting a link between PI3K signaling and the proper function of glucose transporters or hexokinases in glycolysis. Indeed, PI3K/mTOR inhibition effectively suppressed membrane localization of facilitative glucose transporter 1 (GLUT1), which, instead, accumulated in the cytoplasm. Finally, aerobic glycolysis and cell proliferation were down-regulated when GLUT1 gene expression was suppressed by RNAi. Taken together, these results suggest that PI3K/AKT/mTOR signaling is indispensable for the regulation of aerobic glycolysis in EGFR-mutated LAD cells.
Background: EGFR signaling maintains aerobic glycolysis, but the molecular mechanism is still undefined.
Results: Drug inhibition studies reveal that downstream signaling via the PI3K pathway is critical for glucose transport and metabolism.
Conclusion: The PI3K signaling regulates key metabolic activities in EGFR-mutant lung adenocarcinoma.
Significance: These data may guide the development of chemotherapeutic options, including targeting of the PI3K pathway and glucose transporter machinery.
Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer ...(NSCLC)
. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC
. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.
Adsorption profiles of insulin on porous materials and release profiles of insulin entrapped on folded-sheet mesoporous silica (FSM) were studied. Three types of FSM with different pore sizes (3.0, ...6.1, and 9.2
nm) were used as candidates. A simple technique of repeated freezing and thawing resulted in effective adsorption of insulin on mesoporous structures. The amount of adsorbed insulin, estimated by protein assay, increased with an increase in the pore sizes of FSM used. Nitrogen sorption analysis showed that the specific surface area and pore volume decreased according to the insulin adsorption. On the release profile of insulin, the smallest pore size of FSM (3.0) was found to be a suitable material for a fast release of insulin, whereas the medium-pore FSM (6.1) held the insulin inside the pores for a longer time. Consequently, the desired release of insulin could be achieved by selecting the appropriate pore size of FSM.
The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through ...the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
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•LA induces PD-1 expression by Treg cells in highly glycolytic tumors•LA absorbed through MCT1 is a metabolic checkpoint of immune responses•MYC-amplified or liver metastatic tumors augment PD-1+ Treg cells with abundant LA•MCT1 highly expressed by Treg cells provides therapeutic target for immunotherapy
Kumagai et al. show that Treg cells uptake lactic acid in the highly glycolytic tumor microenvironment via MCT1 and robustly express PD-1, resulting in the impairment of PD-1 blockade therapy.
Thomas Mann (1875-1955) ’s novel Doktor Faustus (1947) focuses on the life of the composer Adrian Leverkühn, and was written with the period of World War II. Although several papers have focused on ...the problem of the technique of compositions in those days, described in the novel, little attention has been given to the relation between Doktor Faustus and early music. In this paper, quoting several lines form the novel which related to the early music from Doktor Faustus, I would like to reconsider German early music movement until the 1940’s.
BRAF non-V600E mutations occur in 1% to 2% of NSCLCs. Because of their rarity, the clinical backgrounds and outcomes of cytotoxic chemotherapy or immunotherapy remain unclear, and no targeted ...therapies are approved for BRAF non–V600E-mutant NSCLC.
In this multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia), we evaluated the clinicogenomic characteristics and therapeutic outcomes of BRAF non–V600E-mutant NSCLC.
From March 2015 to November 2021, a total of 11,929 patients with NSCLC were enrolled. BRAF mutations were detected in 380 (3.5%), including the V600E (class I) in 119 (31%) and non-V600E in 261; the non-V600E were functionally classified into class II (122, 32%), class III (86, 23%), and non–classes I to III. Smokers and having concurrent RAS gene family or TP53 mutations were more frequently associated with class II or III than with class I. In patients with class III as compared with class I, the progression-free survival in response to platinum-containing chemotherapies (median, 5.3 versus 11.5 mo, p < 0.01) and the overall survival (median, 14.5 versus 34.8 mo, p < 0.02) were significantly shorter. Furthermore, class IIa mutations were significantly more frequent in our Asian cohort than in previously reported cohorts. The clinicogenomic features associated with class IIa were similar to those associated with class I, and one patient with NSCLC with K601E had a good response to dabrafenib plus trametinib.
Patients with NSCLCs with BRAF non-V600E, especially class III, were associated with poorer therapeutic outcomes than those with V600E. Furthermore, patients with NSCLC with class IIa had distinct clinicogenomic features, and further preclinical and clinical studies are needed to evaluate class IIa mutations as a therapeutic target.
•The frequency of KRAS G12C was 4.0% in Asian patients with NSCLC.•KRAS G12C tumor had higher tumor mutation burden and higher PD-L1 expression.•KRAS G12C-positive NSCLC showed potential sensitivity ...to ICIs.
KRAS G12C is an oncogenic driver mutation, accounting for approximately 14% of Caucasian patients with non-small cell lung cancer (NSCLC). Recently, several KRAS G12C-targeted drugs have been developed; however, the clinico-genomic characteristics of NSCLC patients with KRAS G12C remain unclear.
Based on the large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia) database, the clinico-genomic characteristics and therapeutic outcomes of NSCLC patients with KRAS G12C were evaluated.
From March 2015 to March 2021, 10,023 NSCLC patients were enrolled in LC-SCRUM-Asia. KRAS mutations were detected in 1258 patients (14 %), including G12C in 376 (4.0 %), G12D in 289 (3.1 %) and G12V in 251 (2.7 %). The proportions of males and smokers were higher in patients with KRAS G12C than in those with KRAS non-G12C mutations (males: 73 % vs 63 %, p < 0.001; smokers: 89 % vs 76 %, p < 0.001). KRAS G12C-positive tumors showed a higher tumor mutation burden (TMB) (mean, 8.1 mut/Mb, p < 0.001) and a higher percentage of tumors with programmed cell death ligand-1 (PD-L1) expression ≥50 % (52 %, p = 0.08). The overall survival in patients with KRAS G12C (median, 24.6 months) was not different between patients with other mutation subtypes (G12V: 18.2 months, p = 0.23; G12D: 20.6 months, p = 0.65; other KRAS mutations: 18.3 months, p = 0.20). Among KRAS-mutated patients who received immune checkpoint inhibitors (ICIs), the progression-free survival in G12C-positive patients (median, 3.4 months) was similar to that in G12V-positive patients (4.2 months, p = 0.90), but significantly longer than that in G12D- (2.0 months, p = 0.02) and other KRAS mutation-positive patients (2.5 months, p = 0.02).
The frequencies of KRAS G12C were lower in Asian than in Caucasian NSCLC patients. Among the KRAS-mutated NSCLC patients, G12C-positive tumors showed increased immunogenicity, such as high TMB and high PD-L1 expression, and potential sensitivity to ICIs.
•Classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins.•A possibility that the location of Exon20ins has an impact on effectiveness of TKIs.•Amivantamab may be a promising ...targeted therapy in NSCLC patients with Exon20ins.
In this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes.
The efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial.
Of the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR 95 % CI; TKIs vs docetaxel, 2.16 1.35–3.46; ICIs vs docetaxel, 1.49 1.21–1.84). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR 95 % CI, 0.22 0.07–0.64).
After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.
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