Characteristics of the immune microenvironment and their clinical significance in non-small cell lung cancer patients with ALK-rearranged mutation.

Abstract

Background:

Although immune checkpoint inhibitors (ICIs) are one of the most important treatments for advanced-stage non-small-cell lung cancer (NSCLC), NSCLC patients with ALK-rearranged usually don't obtain a clinical benefit. The reason may be related to the unique tumor microenvironment (TME). We evaluated the characteristics of immune biomarkers of the TME and their prognostic value in ALK-rearranged NSCLC.

Methods:

Tumor samples from patients with ALK-rearranged (N = 39) and EGFR- (N = 40)/KRAS- (N = 30) mutated NSCLC were collected. Immunohistochemistry (IHC) was used to assess the expression of 9 tumor immune markers as well as 6 immune markers of tumor-infiltrating cells. To research the TME of ALK-rearranged NSCLC, EGFR/KRAS-positive patients were used as controls. Furthermore, the correlation between the efficacy and prognosis of patients with advanced-stage (IIIC-IV) ALK rearrangements treated with targeted drugs was analyzed in terms of the TME.

Results:

The proportion of PD-L1+ tumors was lower in ALK-positive NSCLC than in KRAS-positive NSCLC. Besides, the proportion of T cells expressing TIM-3-CD8+ (15.38%), CTLA4-CD8+ (12.82%), LAG3-CD8+ (33.33%) and PD-1-CD8+ (2.56%) in ALK-positive NSCLC was lower than that in EGFR/KRAS-positive NSCLC. The expression of CD3, CD8 T cells and CD20 B cells was lower in ALK-positive NSCLC than in KRAS-positive NSCLC (p < 0.0001, < 0.005, and < 0.001, respectively). Nevertheless, the level of CD4 helper T cells was higher in ALK-positive NSCLC than in EGFR/KRAS-positive NSCLC (p < 0.0001 and p < 0.05, respectively). The repression of TIM3 was higher in ALK-positive NSCLC than in KRAS-positive NSCLC (p < 0.001). In addition, our data showed that high expression of PD-L1 (HR = 0.177, 95% CI 0.038-0.852, p = 0.027) and CTLA4 (HR = 0.196, 95% CI 0.041-0.947, p = 0.043) was related to lower OS in advanced-stage ALK- rearranged NSCLC patients treated with ALK tyrosine kinase inhibitors (TKIs).

Conclusions:

Immunosuppressive status was characteristic of the TME in patients with ALK-positive NSCLC compared with EGFR/KRAS-positive NSCLC. High expression of PD-L1 and CTLA4 was an adverse prognostic factor in advanced-stage ALK-rearranged NSCLC patients treated with ALK-TKIs. Immunotherapy for ALK-rearranged patients requires further exploration and validation by clinical trials.

• Authors: Bo Zhang, Jingtong Zeng, Hao Zhang, Shuai Zhu, Hanqing Wang, Jinling He, Lingqi Yang, Ning Zhou, Lingling Zu, Xiaohong Xu, Zuoqing Song, Song Xu
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 974581 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 36159860 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Zhang, Zeng, Zhang, Zhu, Wang, He, Yang, Zhou, Zu, Xu, Song and Xu.

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CTLA-4 Antigen
• Hepatitis A Virus Cellular Receptor 2
• Immune Checkpoint Inhibitors
• Programmed Cell Death 1 Receptor
• Protein Kinase Inhibitors
• ALK protein, human
• Anaplastic Lymphoma Kinase
• ErbB Receptors
• Proto-Oncogene Proteins p21(ras)

Topics

• Anaplastic Lymphoma Kinase (genetics, metabolism)
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor (genetics)
• CTLA-4 Antigen (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• ErbB Receptors (metabolism)
• Hepatitis A Virus Cellular Receptor 2 (genetics, metabolism)
• Humans
• Immune Checkpoint Inhibitors
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mutation
• Programmed Cell Death 1 Receptor (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Tumor Microenvironment