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 KRAS ‐mutant 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 KRAS ‐G12D 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.

Background: Cytokines have been reported to alter the response to immune checkpoint inhibitors (ICIs) in patients with the tumor in accordance with their plasma concentrations. Here, we aimed to identify the key cytokines which influenced the responses and stimulated resistance to ICIs and tried to improve immunological response and develop novel clinical treatments in non-small cell lung cancer (NSCLC). Methods: The promising predictive cytokines were analyzed via the multi-analyte flow assay. Next, we explored the correlation baseline level of plasma cytokines and clinical outcomes in 45 NSCLC patients treated with ICIs. The mechanism of the potential candidate cytokine in predicting response and inducing resistance to ICIs was then investigated. Results: We found NSCLC with a low baseline concentration of IL-6 in plasma specimens or tumor tissues could derive more benefit from ICIs based on the patient cohort. Further analyses revealed that a favorable relationship between PD-L1 and IL-6 expression was seen in NSCLC specimens. Results in vitro showed that PD-L1 expression in the tumor was enhanced by IL-6 via the JAK1/Stat3 pathway, which induced immune evasion. Notably, an adverse correlation was found between IL-6 levels and CD8⁺ T cells. And a positive association between IL-6 levels and myeloid-derived suppressor cells, M2 macrophages and regulator T cells was also seen in tumor samples, which may result in an inferior response to ICIs. Results of murine models of NSCLC suggested that the dual blockade of IL-6 and PD-L1 attenuated tumor growth. Further analyses detected that the inhibitor of IL-6 stimulated the infiltration of CD8⁺ T cells and yielded the inflammatory phenotype. Conclusions: This study elucidated the role of baseline IL-6 levels in predicting the responses and promoting resistance to immunotherapy in patients with NSCLC. Our results indicated that the treatment targeting IL-6 may be beneficial for ICIs in NSCLC. Graphical

Background: Extensive‐stage small cell lung cancer (ES‐SCLC) is deemed as a fatal malignancy with a poor prognosis. Although immunotherapy has gradually played an important role in the treatment of ES‐SCLC since 2018, ES‐SCLC treatment data and patient outcome before 2018, when chemotherapy served as a fundamental therapeutic strategy, is still meaningful as a summary of the situation regarding previous medical treatment and is a baseline for comparative data. In addition, the prognostic factors of ES‐SCLC have failed to reach a consensus until now. Therefore, this study aimed to evaluate survival and identify the prognostic factors in an ES‐SCLC population.Methods: We retrospectively collected the detailed medical records of 358 patients with ES‐SCLC from January 1, 2011 to December 31, 2018 in a Chinese top‐level cancer hospital. The prognostic factors were evaluated by Cox univariate and multivariate analysis.Results: The median overall survival (OS) of ES‐SCLC patients (N = 358) was 14.0 months, the one‐ and two‐year OS rates were 56.2% and 21.7%, respectively. Moreover, we identified two demographic characters (age ≥ 70, smoking index ≥ 400), one tumor burden factor (bone multimetastasis), two tumor biomarkers (cyfra211, CA125) and two laboratory indexes (decreased Na, PLR < 76) as independent prognostic factors for OS in this patient population. Progression‐free survival (PFS) data of 238 patients was obtained for further analysis, and the median PFS was 6.2 months, and six‐month and one‐year PFS rates were 51.7% and 14.3%, respectively. Elevated cyfra211, decreased Hb and Na were identified as independent prognostic factors for PFS.Conclusions: This study provides real‐world evidence of the survival and prognosis of ES‐SCLC patients which will enable better evaluation and clinical decision‐making in the future.