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Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer.

ABSTRACT: Tyrosine kinase inhibitors (TKI) play a pivotal role in the treatment of non-small-cell lung cancer (NSCLC) with mutations in epidermal growth factor receptor (EGFR) and rearrangements in anaplastic lymphoma kinase (ALK). However, the influences of TKIs on the tumor immune microenvironment (TIM), especially dynamic changes of responders, have not yet been fully elucidated. Therefore, RNA sequencing and whole-exome sequencing were performed on EGFR/ALK-positive NSCLC samples before and after TKI treatment. In combination with neoantigen and mutational-load estimations, xCell and single-sample gene set enrichment analysis (ssGSEA) were used to assess tumor immune-cell infiltration and activity. Furthermore, weighted-gene correlation network analysis and the bottleneck method were used to identify the hub genes that affected treatment-related immune responses. We found that TKI treatment remodeled the TIM in treatment-responsive samples. Profound increases in the rate of anti-tumor cell infiltration and cytotoxicity was observed following TKI treatment, while antigen presentation was limited in ALK-rearranged samples. However, no significant change in anti-tumor cell infiltration or cytotoxicity was found between pre-treatment and post-progression samples. Subsequently, we found that neurofilament heavy (NEFH) mutations were enriched in samples after TKI treatment and were associated with reduced neutrophil infiltration. The cytotoxicity of EGFR-mutant NSCLCs with co-driver TP53 mutation and ALK-rearranged samples with wild-type TP53 seems to be more easily induced by TKI. Finally, the immune-associated score generated by hub genes was positively correlated with immune infiltration, immune activation, and a favorable prognosis. In conclusion, the dynamic changes in the TIM provide clues to drug selection and timing for TKI-immunotherapy combinations.

SUBMITTER: Fang Y

PROVIDER: S-EPMC8288040 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood.MethodsWe performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles.ResultsWhile total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors.ConclusionTargeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.

Project description:PurposeThe great efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been identified in patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, it has not yet been established in postoperative adjuvant therapy.Patients and methodsTo compare the prognosis and toxicity of EGFR-TKI-based adjuvant therapy and non-EGFR-TKI-based adjuvant therapy in resected NSCLC with sensitive EGFR mutations, we performed this meta-analysis of all eligible randomized controlled trials (RCTs).ResultsA comprehensive literature search of electronic databases (from inception to December 31, 2017) was performed. Additionally, abstracts presented at the American Society of Clinical Oncology conferences and World Conference on Lung Cancer held between January 2000 and November 2017 were searched to identify relevant trials. Disease-free survival (DFS), overall survival (OS), and grade 3 or 4 toxicities were analyzed. Five RCTs were selected, and 560 participants were included. This meta-analysis demonstrated that EGFR-TKI-based adjuvant therapy was associated with better DFS compared with non-EGFR-TKI-based therapy (HR =0.52, 95% CI 0.34-0.78, P=0.002). Pooled estimate has showed the trend of superiority of EGFR-TKI-based therapy in the aspect of OS (HR =0.65, 95% CI 0.22-1.91, P=0.43); however, the difference was not significant. The incidence rate of grade 3-4 toxicities of EGFR-TKI-based regimens was significantly higher for rash (OR =10.17, 95% CI 2.37-43.63, P=0.002) but lower for vomiting (OR =0.08, 95% CI 0.01-0.61, P=0.02).ConclusionEGFR-TKI-based therapy was associated with better DFS compared with non-EGFR-TKI-based adjuvant therapy in patients with NSCLC harboring EGFR mutations. A trend was found that EGFR-TKI-based regimen improved the OS, though the difference was not significant. Although more OS data are needed, EGFR-TKI-based treatment has the potential to be an alternative of adjuvant therapy for NSCLC with a sensitive EGFR mutation.

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Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer.

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