The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non‐small cell lung cancer patients with epidermal growth factor receptor mutation

Ma, Lin; Diao, Bowen; Huang, Zhaoqin; Wang, Bin; J, Yu; Meng, Xiangjiao

doi:10.1002/cac2.12229

Cited by 21 publications

(12 citation statements)

References 105 publications

(151 reference statements)

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“…In recent years, immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand programmed cell death‐ligand 1 (PD‐L1) have revolutionized the treatment paradigm of NSCLC and provided an approach for the treatment of refractory patients with NSCLC [ 14 ], particularly patients with KRAS mutations [ 15 , 16 ]. Our previous publication [ 17 ] proved that patients with KRAS ‐mutant NSCLC have a superior response to ICIs due to an inflammatory tumor immune microenvironment (TIME) with adaptive immune resistance.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Zheng

Wang

et al. 2022

Cancer Communications

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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 ...

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Section: Introductionmentioning

confidence: 99%

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

Liu

Zheng

Wang

et al. 2022

Cancer Communications

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“…TMB is the sum of somatic gene-coding errors, base substitutions, and gene insertions or deletions detected per million bases. It is a new marker for evaluating the therapeutic effect of immune checkpoint inhibitors and is related to the effect and prognosis of PD-1 and other immunotherapies [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening

Dong

Bian

et al. 2022

Bioactive Materials

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“…EGFR mutations affect multiple components of the TME, and studies have revealed that activation of the EGFR signaling pathway leads to alterations of TME status, including infiltration of immune cells and expression of immunoregulatory cytokines or exosomes (37). For example, EGFR-mutant tumors tend to have high expression of Tregs and CD73 and low infiltration of CD8+ T cells, indicating an immunosuppressive TME (44). Thus, EGFR-mutant NSCLC may have a distinct TME and identifying key factors involved in anti-tumor responses will provide powerful predictive biomarkers for immunotherapy (45,46).…”

Section: Discussionmentioning

confidence: 99%

Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors

et al. 2022

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BackgroundAlthough immune checkpoint inhibitors (ICIs) generally show poor therapeutic efficacy in patients with epidermal growth factor receptor (EGFR) mutations, certain research indicate that a small proportion of these patients do respond to ICIs. The present study sought to identify the features of patients with EGFR mutations who might benefit from ICIs from multiple studies and discussed the optimal treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations.MethodsThe profiles of 114 advanced NSCLC patients with EGFR mutations who received ICIs treatment were retrospectively reviewed. EGFR subtypes, programmed cell death ligand 1 (PD-L1) expression, and clinical characteristics regarding their impact on the efficacy of ICIs were investigated.ResultsPatients with major EGFR mutations (L858R or 19Del) had a shorter progression-free survival (PFS) and a lower objective response rate (ORR) as compared to patients with rare (20ins or G719X) and other EGFR mutations. Although not statistically significant, median overall survival (OS) tended to be longer in patients with negative (<1%) PD-L1 expression than with positive (≥1%) PD-L1 expression (15.61 vs. 7.40 months, p = 0.138). Median PFS and OS were significantly shorter in heavily treated patients (prior lines of therapy ≥3 lines vs. <3 lines: mPFS, 1.80 vs. 2.50 months, p = 0.003; mOS, 6.70 vs. 14.00 months, p = 0.031). ORR was also lower in patients who had received ≥3 prior lines of therapy compared to in those <3 prior lines of therapy (0.00% vs. 21.67%, p = 0.002).ConclusionPatients with major EGFR mutations showed poorer responses to ICIs than those with rare EGFR mutations. EGFR-mutated patients with lower PD-L1 expression showed a trend towards a longer OS after receiving ICIs. ICIs should be administered as early as possible to previously treated EGFR-mutated NSCLC patients. ICI-based combined therapies may be a direction for treatment of these patient subtypes in the future.

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The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non‐small cell lung cancer patients with epidermal growth factor receptor mutation

Cited by 21 publications

References 105 publications

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

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

Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening

Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors

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