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Pathological Response and Tumor Immune Microenvironment Remodeling Upon Neoadjuvant ALK-TKI Treatment in
Nan Zheng1, Yimin Zhang1, Yue Zeng2
1Department of Respiratory Medicine, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China.
Background:
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI; ALKi) have shown potent antitumor activity in metastatic non-small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+); however, their efficacy in neoadjuvant settings has been poorly explored.
Objective:
This retrospective study aimed to examine the clinical activity and tumor immune microenvironment (TIME) changes of neoadjuvant ALKi therapy.
Methods:
ALK+ NSCLC patients treated with neoadjuvant ALKi at three hospitals in China between February 2018 and January 2023 were assessed. Data on clinical features and radiographic and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pretreatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME.
Results:
A total of 12 patients with stage IIA-IIIB NSCLC who received neoadjuvant ALKi therapy were analyzed. The objective response rate was 91.7% (11/12) and the major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed a significant increase in immune infiltration of CD8+ cells (histochemistry score [H-score]: median 10.51 vs. 24.01, p = 0.028; density: median 128.38 vs. 694.09 cells/mm2, p = 0.028; percentage: median 3.53% vs. 15.92%, p = 0.028) and CD4+ cells (density: median 275.56 vs. 651.82 cells/mm2, p = 0.028; percentage: median 5.98% vs. 10.46%, p = 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB- cells. However, macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy.
Conclusion:
Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME changes by neoadjuvant ALKi therapy and merits further investigation.
Insights
Neoadjuvant anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) therapy shows high response rates and enhances immune cell infiltration in ALK-positive non-small-cell lung cancer (NSCLC). This approach is safe and feasible for resectable NSCLC, warranting further investigation.
Area of Science:
- Oncology
- Immunology
- Thoracic Surgery
Background:
- Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are effective against metastatic ALK-positive non-small-cell lung cancer (NSCLC).
- Their efficacy in the neoadjuvant setting for resectable NSCLC remains underexplored.
Purpose of the Study:
- To evaluate the clinical activity of neoadjuvant ALK-TKI therapy in ALK-positive NSCLC.
- To investigate the impact of neoadjuvant ALK-TKI therapy on the tumor immune microenvironment (TIME).
Main Methods:
- Retrospective analysis of 12 ALK-positive NSCLC patients treated with neoadjuvant ALK-TKI.
- Assessment of clinical, radiographic, and pathological responses.
- Multiplex immunofluorescence analysis of tumor biopsies before and after treatment to assess TIME changes.
Main Results:
- High objective response rate (91.7%) and major pathological response (MPR) rate (75.0%), with 58.3% achieving pathological complete response (pCR).
- Significant increase in CD8+ and CD4+ T-cell infiltration post-treatment.
- Minimal changes observed in macrophage populations (M1 and M2).
Conclusions:
- Neoadjuvant ALK-TKI therapy demonstrates promising MPR rates and enhances immune cell infiltration in ALK-positive resectable NSCLC.
- The therapy is safe and feasible, supporting its further investigation.
- This study provides insights into neoadjuvant ALK-TKI-induced TIME modulation.
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