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Tumour microenvironment changes after osimertinib treatment resistance in non-small cell lung cancer
Ruoshuang Han1, Haoyue Guo2, Jinpeng Shi2
1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China; Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Background:
Growing evidence suggests that acquired resistance to targeted therapy in non-small cell lung cancer patients is linked to the mutual domestication between the tumour and its surrounding microenvironment.
Aim:
Our study aims to explore the remodelling of tumour microenvironment after osimertinib treatment resistance.
Methods:
We took RNA-seq-based tumour immune infiltration analysis using the TIMER 2.0. We carried out flow cytometry assay and real-time cell analysis to explore the interaction between tumour cells and immune cells. In addition, we analysed exosomes via miRNA-seq and label-free proteomics.
Results:
Immune infiltration estimation showed a significant decrease in the immune score (P < 0.001), microenvironment score (P < 0.001) and CD8+ T cells (P < 0.05), but an increase in M0 macrophages (P < 0.01) at osimertinib resistance compared to pre-treatment patients. It was demonstrated that exosomes from H1975OR cells could be taken up by macrophages and drove their polarisation towards the M2 phenotype, and the polarised M2 macrophages could reduce the inhibitory effect on tumour cell proliferation. Pre-activated peripheral blood mononuclear cells exhibited a more potent killing effect on H1975OR cells. We also detected a decrease in CD4+HLA-DR- T cells and an increase in CD4+PD1+ T cells after being co-cultured with H1975OR derived exosomes or conditioned medium. Further miRNA-seq and proteomics analysis of exosomes demonstrated that mir-1258-3p and miR-17-5p might participate in this interaction.
Conclusions:
An immunosuppressive environment, characterised by decreased T cell infiltration and activation, whereas increased macrophage infiltration and M2 polarisation, was identified at osimertinib resistance. This interaction may be carried out by tumour-derived exosomes.
Insights
Acquired resistance to osimertinib in non-small cell lung cancer is linked to immune changes. Tumour exosomes promote an immunosuppressive microenvironment by driving macrophage M2 polarization, hindering T cell activity.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Acquired resistance to targeted therapies like osimertinib in non-small cell lung cancer (NSCLC) is a significant clinical challenge.
- Emerging evidence highlights the critical role of the tumor microenvironment (TME) in mediating this resistance.
- The dynamic interplay between tumor cells and immune cells within the TME is increasingly recognized as a key factor.
Purpose of the Study:
- To investigate the alterations in the tumor microenvironment following the development of osimertinib resistance in NSCLC.
- To elucidate the mechanisms by which tumor cells and immune cells interact in the resistant TME.
- To identify potential molecular mediators, such as exosomes, involved in TME remodeling during osimertinib resistance.
Main Methods:
- RNA-sequencing based tumor immune infiltration analysis using TIMER 2.0.
- Flow cytometry and real-time cell analysis to assess tumor-immune cell interactions.
- Exosome isolation followed by miRNA sequencing (miRNA-seq) and label-free proteomics.
Main Results:
- Osimertinib resistance was associated with decreased immune and microenvironment scores, reduced CD8+ T cells, and increased M0 macrophages.
- Tumor-derived exosomes promoted macrophage polarization to the M2 phenotype, which in turn reduced the inhibitory effect on tumor cell proliferation.
- Exosomes also modulated T cell populations, decreasing CD4+HLA-DR- T cells and increasing CD4+PD1+ T cells, suggesting immune suppression.
Conclusions:
- Osimertinib resistance in NSCLC is characterized by an immunosuppressive TME with reduced T cell infiltration/activation and increased M2-polarized macrophages.
- Tumor-derived exosomes appear to mediate these TME changes, potentially through specific miRNAs like miR-1258-3p and miR-17-5p.
- Understanding these exosome-mediated interactions is crucial for developing strategies to overcome targeted therapy resistance.
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