Abstract
Simple SummaryNon-small cell lung cancer is the most common type of lung cancer. Anaplastic Lymphoma Kinase (ALK) rearrangements have been found in 5–6% of non-small cell lung cancers. While ALK rearranged non-small cell lung cancer is exquisitely sensitive to ALK directed targeted therapies, it is generally resistant to immune-based therapies. We aim to describe the mechanisms by which ALK-rearranged non-small cell lung cancers escape host immunity and are thereby unresponsive to immunotherapies. Furthermore, we describe new immunotherapy strategies and the promises and challenges in incorporating these into clinical practice.Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene have been implicated in 5–6% of all non-small cell lung cancers. ALK-rearranged non-small cell lung cancers are sensitive to ALK-directed tyrosine kinase inhibitors, but generally resistant to single-agent immune checkpoint inhibitors. Here, we aim to describe the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. We report pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describe the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer.
Highlights
Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers and is one of the leading causes of cancer-related mortality worldwide [1,2]
anaplastic lymphoma kinase (ALK)-rearranged NSCLC comprise 5–6% of all NSCLC and are exquisitely sensitive to ALK-directed tyrosine kinase inhibitor (TKI), four of which are approved for treatment of patients with advanced ALK-rearranged NSCLC
Despite pre-clinical studies suggesting up-regulation of programmed cell death ligand-1 (PD-L1) in ALK-rearranged NSCLC, single-agent Immune checkpoint inhibitors (ICI) have not shown clinical benefit in retrospective studies in the treatment of ALK-rearranged NSCLC. This is thought to be due to an ALK driven immunosuppressive TME characterized by scarce CD8+ TIL and increased FOXP3+ T regulatory cells [74]
Summary
Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers and is one of the leading causes of cancer-related mortality worldwide [1,2]. In 2007, NSCLC tumors harboring mutations in the anaplastic lymphoma kinase (ALK) gene were identified [3]. ALK rearrangements result in an oncogenic driver in 5–6% of NSCLC cases [4], representing approximately 100,000 new cases of lung cancer annually worldwide. Patients with ALKrearranged NSCLC are characterized by an absence of smoking or light smoking history and a younger age at diagnosis (median age at diagnosis: 54 years) [5]
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