Nuclear AhR and membranous PD-L1 in predicting response of non-small cell lung cancer to PD-1 blockade

Dear Editor,Programmed cell death 1 ligand 1(PD-L1)has been used as a biomarker for immune checkpoint inhibitors(ICIs)which exert durable efficacy in non-small cell lung cancer(NSCLC).^(1,2)However,many PD-L1-high patients only marginally respond to,and PD-L1-low patients still benefit from,ICIs.^(3,4)

Approximation by random weighting method for M-test in linear models

The M-test has been in common use and widely studied in testing the linear hypotheses in linear models. However, the critical value for the test is usually related to the quantities of the unknown error distribution and the estimate of the nuisance parameters may be rather involved, not only for the M-test method but also for the existing bootstrap methods. In this paper we suggest a random weighting resampling method for approximating the null distribution of the M-test statistic. It is shown that, under both the null and the local alternatives, the random weighting statistic has the same asymptotic distribution as the null distribution of the M-test. The critical values of the M-test can therefore be obtained by the random weighting method without estimating the nuisance parameters. A distinguished feature of the proposed method is that the approximation is valid even the null hypothesis is not true and the power evaluation is possible under the local alternatives.

Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1

Indoleamine 2,3-dioxygenase 1(IDO1),the enzyme that catabolizes tryptophan(Trp)metabolism to promote regulatory T cells(Tregs)and suppress CD8+T cells,is regulated by several intrinsic signaling pathways.Here,we found that tobacco smoke,a major public health concern that kills 8 million people each year worldwide,induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo.The carcinogen nicotine-derived nitrosaminoketone(NNK)was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun,which has a binding site for the IDO1 promoter.The NNK receptorα7 nicotinic acetylcholine receptor(α7nAChR)was required for NNK-induced c-Jun activation and IDO1 upregulation.In A/J mice,NNK reduced CD8+T cells and increased Tregs.Clinically,smoker patients with non-small-cell lung cancer(NSCLC)exhibited high IDO1 levels and low Trp/kynurenine(Kyn)ratios.In NSCLC patients,smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1.These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis,and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients,whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.