Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in East Asian patients with non-small cell lung cancer

Objective:The aim of this study was to investigate how the tumor immune microenvironment differs regarding tumor genomics,as well as its impact on prognoses and responses to immunotherapy in East Asian patients with non-small cell lung cancer(NSCLC).Methods:We performed an integrated analysis using publicly available data to identify associations between anti-programmed death 1(PD-1)/programmed death-ligand 1(PD-L1)immunotherapy efficacy and classic driver oncogene mutations in East Asian NSCLC patients.Four pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+tumor-infiltrating lymphocytes(TILs).Immune infiltrating patterns were also established for genomic NSCLC subgroups using the CIBERSORT algorithm.Results:Based on East Asian NSCLC patients,TIDE analyses revealed that for anti-PD-1/PD-L1 immunotherapy,epidermal growth factor receptor(EGFR)-mutant and anaplastic lymphoma kinase(ALK)-rearranged tumors yielded inferior responses;however,although Kirsten rat sarcoma viral oncogene homolog(KRAS)-mutant tumors responded better,the difference was not statistically significant(EGFR:P=0.037;ALK:P<0.001;KRAS:P=0.701).Pooled and clinical cohort analyses demonstrated tumor immune microenvironment heterogeneities correlated with oncogenic patterns.The results showed remarkably higher PD-L1-and TIL-positive KRAS-mutant tumors,suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune resistance.However,the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1-/TIL-tumors,suggesting an uninflamed phenotype with immunological ignorance.Notably,similar to triple wild-type NSCLC tumors,EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype,suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy(P<0.05).Furthermore,the CIBERSORT algorithm results revealed that EGFR-mutant and ALK-rearranged tumors were characterized by an enriched resting memory CD4+T cell population(P<0.001),as well as a lack of CD8+T cells(P<0.01),and activated memory CD4+T cells(P=0.001).Conclusions:Our study highlighted the complex relationships between immune heterogeneity and immunotherapeutic responses in East Asian NSCLC patients regarding oncogenic dependence.

A novel recurrence-associated metabolic prognostic model for risk stratification and therapeutic response prediction in patients with stage Ⅰ lung adenocarcinoma

Objective:The proportion of patients with stageⅠlung adenocarcinoma(LUAD)has dramatically increased with the prevalence of low-dose computed tomography use for screening.Up to 30%of patients with stageⅠLUAD experience recurrence within 5 years after curative surgery.A robust risk stratification tool is urgently needed to identify patients who might benefit from adjuvant treatment.Methods:In this first investigation of the relationship between metabolic reprogramming and recurrence in stageⅠLUAD,we developed a recurrence-associated metabolic signature(RAMS).This RAMS was based on metabolism-associated genes to predict cancer relapse and overall prognoses of patients with stageⅠLUAD.The clinical significance and immune landscapes of the signature were comprehensively analyzed.Results:Based on a gene expression profile from the GSE31210 database,functional enrichment analysis revealed a significant difference in metabolic reprogramming that distinguished patients with stageⅠLUAD with relapse from those without relapse.We then identified a metabolic signature(i.e.,RAMS)represented by 2 genes(ACADM and RPS8)significantly related to recurrence-free survival and overall survival times of patients with stageⅠLUAD using transcriptome data analysis of a training set.The training set was well validated in a test set.The discriminatory power of the 2 gene metabolic signature was further validated using protein values in an additional independent cohort.The results indicated a clear association between a high risk score and a very poor patient prognosis.Stratification analysis and multivariate Cox regression analysis showed that the RAMS was an independent prognostic factor.We also found that the risk score was positively correlated with inflammatory response,the antigen-presenting process,and the expression levels of many immunosuppressive checkpoint molecules(e.g.,PD-L1,PD-L2,B7-H3,galectin-9,and FGL-1).These results suggested that high risk patients had immune response suppression.Further analysis revealed that anti-PD-1/PD-L1 immunotherapy did not have significant benefits for high risk patients.However,the patients could respond better to chemotherapy.Conclusions:This study is the first to highlight the relationship between metabolic reprogramming and recurrence in stageⅠLUAD,and is the first to also develop a clinically feasible signature.This signature may be a powerful prognostic tool and help further optimize the cancer therapy paradigm.

PD-L1 expression and smoke exposure as biomarkers for optimizing adjuvant therapy for patients with resected limited-stage small-cell lung carcinoma

Small-cell lung cancer(SCLC)is a highly malignant cancer with characteristics of rapid growth,abundant angiogenesis,and early distant metastasis that accounts for about 15%of lung cancers.With the wide application of low-dose computed tomography screening in recent years,the incidence of early limited-stage SCLC has increased dramatically.

Magnetotail dipolarization fronts and particle acceleration:A review

In this paper, the particle acceleration processes around magnetotail dipolarization fronts(DFs) were reviewed. We summarize the spacecraft observations(including Cluster, THEMIS, MMS) and numerical simulations(including MHD, testparticle, hybrid, LSK, PIC) of these processes. Specifically, we(1) introduce the properties of DFs at MHD scale, ion scale, and electron scale,(2) review the properties of suprathermal electrons with particular focus on the pitch-angle distributions,(3)define the particle-acceleration process and distinguish it from the particle-heating process,(4) identify the particle-acceleration process from spacecraft measurements of energy fluxes, and(5) quantify the acceleration efficiency and compare it with other processes in the magnetosphere(e.g., magnetic reconnection and radiation-belt acceleration processes). We focus on both the acceleration of electrons and ions(including light ions and heavy ions). Regarding electron acceleration, we introduce Fermi,betatron, and non-adiabatic acceleration mechanisms;regarding ion acceleration, we present Fermi, betatron, reflection, resonance, and non-adiabatic acceleration mechanisms. We also discuss the unsolved problems and open questions relevant to this topic, and suggest directions for future studies.

KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer

Background:Although immune checkpoint inhibitors(ICIs)against programmed cell death protein 1(PD-1)and its ligand PD-L1 have demonstrated potency towards treating patients with non-small cell lung carcinoma(NSCLC),the potential association between Kirsten rat sarcoma viral oncogene homolog(KRAS)oncogene substitutions and the efficacy of ICIs remains unclear.In this study,we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism.Methods:The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort(n=74),and confirmed with a mouse model.In addition,the tumor immune microenvironment(TIME)of KRASmutant NSCLC,such as CD8+tumor-infiltrating lymphocytes(TILs)and PD-L1 level,was investigated.Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME.Furthermore,interventions that improved TIME were developed to increase responsiveness to ICIs.Results:We observed the inferior efficacy of ICIs in KRAS-G12D-mutant NSCLC.Based upon transcriptome data and immunostaining results from KRAS-mutant NSCLC,KRAS-G12D point mutation negatively correlated with PD-L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+TILs,which in turn yielded an immunosuppressive TIME.The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS-G12D mutation suppressed PD-L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down-regulating high mobility group protein A2(HMGA2)level.Notably,paclitaxel,a chemotherapeutic agent,upregulated HMGA2 level,and in turn,stimulated the secretion of CXCL10/CXCL11.Moreover,PD-L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD-L1 inhibitor monotherapy in a mouse model with KRAS-G12D-mutant lung adenocarcinoma.Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+TILs via the up-regulation of CXCL10/CXCL11 levels.Results of clinical study also revealed the superior efficacy of chemo-immunotherapy in patients with KRAS-G12D-mutant NSCLC compared with ICI monotherapy.Conclusions:Our study elucidated the molecular mechanism by which KRASG12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC.Importantly,our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS-G12D-mutant NSCLC.

S100A7 attenuates immunotherapy by enhancing immunosuppressive tumor microenvironment in lung squamous cell carcinoma

Dear Editor,In recent years,the rapid development of immunotherapy has brought survival benefits for lung squamous cell carcinoma(LUSC)patients who have rare treatment options.Nevertheless,there are still some patients with immunotherapy resistance,which is the root cause of the low benefit rate and disease progression of the overall population,and it is an urgent problem to be solved.Except for tumor mutation burden,the tumor immune microenvironment(TIME)as characterized by infiltration of CD8+tumor-infiltrating lymphocytes(TILs)and PD-L1 expression has been associated with the efficacy of immune checkpoint inhibitors(ICIs).In our previous studies,we have demonstrated that psoriasin,also known as S100 calcium-binding protein A7(S100A7),not only accelerates tumor progression via the activation of the p-Erk pathway in LUSC and the p-Erk and p-FAK pathways in esophageal squamous cell carcinomas(ESCC)but also remodels the tumor microenvironment by promoting angiogenesis and M2 macrophage infiltration in ESCC.1,2 However,the role of S100A7 in the TIME and immunotherapy efficacy in LUSC remains to be elucidated.