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 immuneassociated 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.

Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer

“…This study was approved by the Nanfang Hospital Ethics Review Board. Thirty fresh samples histologically diagnosed with nonmetastatic colon cancer at the SYSUCC (Guangzhou, China) were included, and RNA extraction and sequencing were performed as described previously [ 40 ]. The count values of RNA-sequencing data were transformed using the “voom” algorithm after gene symbol transformation (based on Ensembl ID) in order to convert count data to values similar to those resulting from microarrays [ 41 ].…”

Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy

“… 144 In addition, they shape the tumor environment and may switch it from immunosuppressive or tumor-permissive to immune-stimulating and tumor-intolerant. 7 , 145–147 …”

“…Erlotinib plus anti-PD-1 showed superior therapeutic efficacy compared to single treatments. 145 , 157 However, despite the fact that the oncogenic signaling may induce PD-L1 upregulation in NSCLC, the superiority of immune checkpoint inhibitors in advanced EGFR-mutant NSCLC is only moderate in patients. Indeed, multiple mechanisms, including dynamic immune TME, PD-L1 expression levels and low tumor mutational burden, may account for the conflicting results regarding associations between the EGFR mutation status and response rates with PD-L1/PD-1 inhibitors.…”

“… 162–164 Thus, immunotherapy with an anti-PD1 antibody administered after crizotinib cured almost 90% of mice bearing orthotropic NSCLCs. 145 , 165 , 166 …”

Immunological effect of tyrosine kinase inhibitors on the tumor immune environment in non‑small cell lung cancer (Review)

“…Recently, whole-exome and RNA sequencing indicated that immune-related genes were altered in response to ALK TKI treatment. Antigen presentation genes, IFN-γ signaling genes, inhibitory checkpoint genes, and stimulatory checkpoint genes increased apparently after response to ALK TKIs ( Table I ) ( 16 ).…”