Characterizing the immune tumor microenvironment in ALK fusion-positive lung cancer: state-of-the-art and therapeutical implications

ABSTRACT

Introduction

Approximately 5% of non-small cell lung cancer (NSCLC), exhibits anaplastic lymphoma kinase (ALK) rearrangements. EML4-ALK fusions account for over 90% of ALK rearrangements in NSCLC. The advent of treatment targeting ALK has significantly improved survival rates in patients with advanced ALK-positive NSCLC. However, the emergence of resistance mechanisms and the subsequent progression disease inevitably occurs. The tumor immune microenvironment (TIME) plays a pivotal role in lung cancer, influencing disease development, patient’s outcomes, and response to treatments.

Areas covered

The aim of this review is to provide a comprehensive characterization of the TIME in ALK rearranged NSCLC and its intrinsic plasticity under treatment pressure.

Expert opinion

Recognizing the fundamental role of the TIME in cancer progression has shifted the paradigm from a tumor cell-centric perspective to the understanding of a complex tumor ecosystem. Understanding the intricate dynamics of the TIME, its influence on treatment response, and the potential of immunotherapy in patients with ALK-positive NSCLC are currently among the primary research objectives in this patient population.

KEYWORDS:

• Anaplastic lymphoma kinase
• immunotherapy
• non-small cell lung cancer
• targeted therapy
• tumor immune microenvironment

Acknowledgments

LB and AA are supported by grants from Associazione Pietro Casagrande ONLUS. L.B. and M.M. are supported by Piano Nazionale di Ripresa e Resilienza (PNRR) projects HEAL Italia and INNOVA.

Article highlights

• Patients with ALK translocated disease have peculiar TIME features, i.e. a reduced functionality of effector T cells and an increased expression of PD-1, LAG-3, and TIM-3.

• ALK positive NSCLC that develop resistance to ALK TKIs show a low presence of TCD8+ and high presence of Treg in TIME. In NSCLC responsive to ALK TKIs, an increase in TCD8+ CD3+ cells, natural killer and gamma delta cells was observed.

• Modified IL-2, CAR-T cell therapies, and the combination of novel immune agents with anti-ALK TKIs are examples of treatments that are currently under investigation.

Declaration of interest

L Belluomini received speakers’ fees from AstraZeneca, Merck Sharp & Dohme, and Roche, outside the submitted manuscript, travel fees from Takeda. S Pilotto received honoraria or speakers’ fees from AstraZeneca, Eli Lilly, Bristol-Myers Squibb, Merck, Takeda, Amgen, Novartis, and Roche, outside the submitted manuscript. L Belluomini and A Avancini are supported by grants from Associazione Pietro Casagrande ONLUS. L Derosa is supported by grants from ARC foundation.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.