No abstract

A PT regimen consisting of INH combined with RFP for 3 consecutive months is reasonable for use in schools. Discrimination, worry about adverse drug reactions, a low parental education level, and accepting the opinion of a non-TB specialist are all factors that may increase the risk for treatment abandonment among LTBI cases. To overcome psychological obstacles is critical for improving treatment adherence.

Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in LKB1-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult-to-treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1 driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1 driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFN-γ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.

Background Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). Methods A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. Results Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). Conclusions Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.