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; immune checkpoint inhibitors; immunotherapy; microenvironment; non-small cell lung cancer (NSCLC).

Figure 1

Interaction among the bone, immune system, and cancer cells. CAF: cancer-associated fibroblasts; CAECs: cancer associated endothelial cells; Th: T helper; Treg: regulatory T cells; PD-1: programmed-death 1; PD-L1: PD-ligand (PD-L1); CTLA4: cytotoxic T lymphocyte-associated protein 4; RANK: receptor-activator of nuclear kappaB; RANKL: receptor-activator of nuclear kappaB ligand; PTHrP: parathyroid hormone-related peptide; PGE2: prostaglandin E2; CCL2: chemokine (C-C motif) ligand 2; IDO–1: indoleamine 2,3-dioxygenase-1; IL: interleukin; TGF-beta: transforming growth factor-beta; IFN-gamma: interferon-gamma; TDE: tumor derived exosome; EVs: extracellular vesicles.