Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer
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), es...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2021.1951019 |
| _version_ | 1819283939227860992 |
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| author | Yisheng Fang Yuanyuan Wang Dongqiang Zeng Shimeng Zhi Tingting Shu Na Huang Siting Zheng Jianhua Wu Yantan Liu Genjie Huang Yichen Xue Jianping Bin Yulin Liao Min Shi Wangjun Liao |
| author_facet | Yisheng Fang Yuanyuan Wang Dongqiang Zeng Shimeng Zhi Tingting Shu Na Huang Siting Zheng Jianhua Wu Yantan Liu Genjie Huang Yichen Xue Jianping Bin Yulin Liao Min Shi Wangjun Liao |
| author_sort | Yisheng Fang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T01:39:27Z |
| format | Article |
| id | doaj.art-a736454c3cb64c399236b38df82072c0 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-24T01:39:27Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-a736454c3cb64c399236b38df82072c02022-12-21T17:22:05ZengTaylor & Francis GroupOncoImmunology2162-402X2021-01-0110110.1080/2162402X.2021.19510191951019Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancerYisheng Fang0Yuanyuan Wang1Dongqiang Zeng2Shimeng Zhi3Tingting Shu4Na Huang5Siting Zheng6Jianhua Wu7Yantan Liu8Genjie Huang9Yichen Xue10Jianping Bin11Yulin Liao12Min Shi13Wangjun Liao14Southern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversityTyrosine 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.http://dx.doi.org/10.1080/2162402X.2021.1951019tumor immune microenvironmentnon-small-cell lung canceregfr mutationalk rearrangementtyrosine kinase inhibitors |
| spellingShingle | Yisheng Fang Yuanyuan Wang Dongqiang Zeng Shimeng Zhi Tingting Shu Na Huang Siting Zheng Jianhua Wu Yantan Liu Genjie Huang Yichen Xue Jianping Bin Yulin Liao Min Shi Wangjun Liao Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer OncoImmunology tumor immune microenvironment non-small-cell lung cancer egfr mutation alk rearrangement tyrosine kinase inhibitors |
| title | Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer |
| title_full | Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer |
| title_fullStr | Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer |
| title_full_unstemmed | Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer |
| title_short | Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer |
| title_sort | comprehensive analyses reveal tki induced remodeling of the tumor immune microenvironment in egfr alk positive non small cell lung cancer |
| topic | tumor immune microenvironment non-small-cell lung cancer egfr mutation alk rearrangement tyrosine kinase inhibitors |
| url | http://dx.doi.org/10.1080/2162402X.2021.1951019 |
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