Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment …

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Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications


Abstract
Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, which reduce the patient’s quality of life. Recently, the treatment of advanced NSCLC has radically changed due to the advent of immunotherapy. Immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy have become the main therapeutic strategy for advanced or metastatic NSCLC without driver gene mutations. Since survival has increased, it has become even more important to treat bone metastasis to prevent SRE. We know that the presence of bone metastasis is a negative prognostic factor. The lower efficacy of immunotherapy treatments in BoM+ patients could be induced by the presence of a particular immunosuppressive tumor and bone microenvironment. This article reviews the most important pre-clinical and clinical scientific evidence on the reasons for this lower sensitivity to immunotherapy and the need to combine bone target therapies (BTT) with immunotherapy to improve patient outcome.

Keywords: bone metastasis, immunotherapy, immune checkpoint inhibitors, microenvironment, non-small cell lung cancer (NSCLC)
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1. Introduction
Lung cancer is the leading cause of cancer-related death [1]. In recent years, there has been an improvement in cancer biology and immune system knowledge. In particular, the treatment of non-small cell lung cancer (NSCLC) has radically changed due to the introduction of new molecules with a molecular target and the advent of immunotherapy. Immune checkpoint inhibitors (ICIs), which target programmed-death 1 (PD1) and PD-ligand (PD-L1), either used alone or in combination with chemotherapy have become the main therapeutic strategies for advanced or metastatic NSCLC without driver gene mutations [2,3]—since progression free survival (PFS) and overall survival (OS) has improved. Nivolumab, atezolizumab, and pembrolizumab are recommended options for patients who progress after platinum-doublet chemotherapy. The Food and Drug Administration (FDA) approved nivolumab for this indication in October 2015 and atezolizumab in October 2016. Pembrolizumab received FDA approval for this indication in October 2015 with a limitation for PD-L1 positive tumors (with the accompained diagnostic IHC 22C3 pharmaDX test). As of today, pembrolizumab alone is the standard first-line therapy for patients with PD-L1 expression >50% (FDA approval in October 2016), whereas pembrolizumab plus platinum-base chemotherapy is the treatment of choice for patients with PDL-L1 < 50% (FDA approval for non-squamous NSCLC in May 2017 and for squamous in October 2018). Recently (May 2020) nivolumab plus ipilimumab, given with two cycles of platinum-doublet chemotherapy, was approved by the FDA as a first-line treatment for metastatic NSCLC regardless of histology and PD-L1 expression.

Recently, some clinical factors, such as performance status and metastatic sites, emerged as potential predictors for immunotherapy efficacy [4,5,6]. In this narrative review, we pointed out the impact of bone metastatic site.

The incidence of bone metastasis in NSCLC varies—according to the studies taken into consideration—ranging from 20% to more than 60%. Thanks to the improvement of diagnostic techniques (e.g., PET-CT scan) associated with increased survival, the incidence of bone metastasis seems to be increased. In fact, 20–30% of NSCLC patients have bone metastasis at diagnosis and a further 35–40% of cases develop bone metastasis during the course of their disease [7,8]. We know that this metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, all of which reduce the patient’s quality of life and performance status [9]. Bone metastasis usually indicates a poor prognosis for patients with lung cancer [10].

In the last decades, evidence has been published that indicates that bone marrow also functions in regulating the immune system and trafficking immune cells (regulatory T cells, T cells, B cells, dendritic cells, natural killer T cells, myeloid-derived suppressor cells, and mesenchymal stem cells) [11]. Bone marrow, therefore, can be considered an immune system regulator and could potentially influence the response to immunotherapy. This is the new concept of osteoimmuno-oncology (OIO), which refers to interactions between bone, immune, and tumor cells in the bone metastatic microenvironment [12].

To our knowledge, however, none of the previous randomized control trials have ever evaluated the impact of bone involvement in patients treated with immune checkpoint inhibitors nor stratified patients based on bone metastasis. Only about 1% (6/561) of publications with approved immunotherapies in breast, prostate, lung cancer, and melanoma patients report results on bone metastasis. Thus, the impact of BoM on ICI treatment has remained poorly studied. It was found that the tumor and bone microenvironment play an important role. Several studies [6,13,14,15] suggest that bone involvement may be a negative prognostic factor and the presence of BoM could be predictive of a poor response to ICIs.

In the last few years, it has also been hypothesized that the interaction between the tumor, the immune system, and the bone may occur through the presence of extracellular vesicles (EVs) that carry information through the bloodstream.

The aims of this narrative review are: (1) describe the biological theories concerning the microenvironment of bone metastasis and the interaction between bone, the immune system, and neoplastic cells; (2) discuss the published clinical data of patients with NSCLC and bone metastasis treated with immunotherapy (alone or in combination with chemotherapy and/or bone-targeted therapy); and (3) discuss new perspectives in the field of osteoimmunoncology.




https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9224636/