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

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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.

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Rina Hui, Takayasu Kurata, Silvia Novello … (2018)

First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.

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Author and article information

Contributors

Bo Zhang: URI : https://loop.frontiersin.org/people/1572349

Hao Zhang: URI : https://loop.frontiersin.org/people/1633597

Shuai Zhu: URI : https://loop.frontiersin.org/people/1225991

Hanqing Wang: URI : https://loop.frontiersin.org/people/1633600

Ning Zhou: URI : https://loop.frontiersin.org/people/1558555

Lingling Zu: URI : https://loop.frontiersin.org/people/1385823

Xiaohong Xu: URI : https://loop.frontiersin.org/people/1634063

Zuoqing Song: URI : https://loop.frontiersin.org/people/1506296

Song Xu: URI : https://loop.frontiersin.org/people/795214

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 08 September 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 974581

Affiliations

[1] ¹ Department of Lung Cancer Surgery, Tianjin Medical University General Hospital , Tianjin, China

[2] ² Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital , Tianjin, China

[3] ³ Colleges of Nursing, Tianjin Medical University , Tianjin, China

Author notes

Edited by: Xuelei Ma, Sichuan University, China

Reviewed by: Arutha Kulasinghe, The University of Queensland, Australia; Qing Zhou, Guangdong Provincial People’s Hospital Lung Cancer Institute, China

*Correspondence: Song Xu, xusong198@ 123456hotmail.com ; Zuoqing Song, thoracic_expert@ 123456aliyun.com

†These authors have contributed equally to this work

This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

Article

DOI: 10.3389/fimmu.2022.974581

PMC ID: 9494286

PubMed ID: 36159860

SO-VID: 87796032-e3ce-4afc-b146-5fe2f1c0ed16

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 21 June 2022

Date accepted : 10 August 2022

Page count

Figures: 7, Tables: 1, Equations: 0, References: 50, Pages: 12, Words: 4172

Funding

Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;

Funded by: Tianjin Science and Technology Program , doi 10.13039/501100019065;

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

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Abstract

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