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/
Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment …
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Discussion and Future Perspectives
While the majority of breast and prostate cancer patients with bone metastasis are treated with bone targeted therapy, currently only about 50–60% of patients with NSCLC are treated with bone-specific drugs [7,14]. This is due to the fact that, until a few years ago, the prognosis was so severe that it, unfortunately, dissuaded oncologists from prescribing BTT. With the introduction of molecular therapies—but, above all, of immunotherapy—survival has significantly increased. This change of scenario has therefore led to a conceptual shift. First, with the survival gain, the likelihood of developing bone metastasis during the course of the disease also increases. Consequently, more patients may experience SREs. As is known, SREs have a negative impact on the quality of life, so it is necessary to treat most patients with bone resorptive drugs. The second point directly concerns the greater knowledge of the close interconnection between bone marrow and the immune system. In this context, in fact, osteoimmuno-oncology has developed and has hypothesized that adequate treatment of patients with BoM+ and ICI is not only possible but is essential to guarantee them an increase in ORR, PFS, and OS. For these reasons, we believe that there is, or should be, a therapeutic shift in these patients.
The pre-clinical data reported are the result of studies on cellular interactions and pathways involved in the development of osteolytic bone metastasis mainly of breast cancer. Although there are fewer studies in NSCLC, these models are likely to be valid. It is confirmed that the RANK-RANKL pathway is the main pathway responsible for bone resorption. At the same time, more and more evidence demonstrates a close interplay between bone marrow and the immune system (Figure 1). In fact, one system regulates the other.
Therapy with immune checkpoint inhibitors fits into this context. The data available so far demonstrate that bone metastasis is an independent prognostic factor with poor outcomes in patients treated with immunotherapy. In view of the retrospective nature of the clinical data available to us, or the small prospective data, it is clear that there are modest discrepancies in the prognostic impact of ICIs and BTT in these patients. However, most of the trials indicate that the effectiveness of immunotherapy, especially when considered as monotherapy, could be modulated by the tumor and bone microenvironment.
More and more data support the idea that a hostile (cold) tumor microenvironment is created in patients with BoM+, which would reduce the effectiveness of immunotherapy. Some authors believe that the use of bone therapy, in particular bone target therapies, could reverse the resistance to immunotherapy by breaking the “vicious cycle” (Figure 1). Theoretically, an anti-RANK therapy associated with ICIs could be more synergistic. It is clear that larger prospective clinical studies are needed to confirm the hypothesis that emerged from some retrospective studies.
The clinical studies presented, in fact, have important limits due to the retrospective nature, the sample size of each single study, and the heterogeneity of patients included (first line, subsequent lines, ICI associated or not with other chemotherapeutic/antiangiogenic drugs).
The scope of the association of palliative bone radiation therapy with ICIs in BoM+ patients should also be explored with dedicated prospective studies.
Due to a “cold” TME, patients with BoM may benefit little from the combination of different types of immunotherapies, since ICIs require the presence of effector lymphocytes at the TME level to be effective. While there are drugs that allow the interruption of the “vicious cycle”, transforming the TME from “cold” to “hot” could hypothetically be more promising. For example, bisphosphonates or denosumab that inhibit osteoclast-mediated bone resorption through the inhibition of the pathway of nuclear factor kappa-B ligand receptor (RANKL) could be some of the options. Some chemotherapeutic agents are also capable of reducing immunosuppressive Tregs and inducing apoptosis of myeloid derived suppressor cells (MDSCs). Antiangiogenic drugs, normalizing vascularization, and reducing tumor hypoxia can reduce the production of immunosuppressive cytokines such as IL6, IL10, and IDO.
Thus, the combination of ICIs with chemotherapy, anti-angiogenesis, or bisphosphonates/denosumab could give therapeutic advantages to patients with BoM.
Based on new knowledge, new drug associations could be developed in the future.
Understanding osteoclast signaling in bone metastasis could help to identify new targets for drug discovery [40], and there are currently drug candidates in different phases of development that are targeting osteoclasts, such as SRC, DKK-1 (dickkopf WNT signaling pathway inhibitor 1), and Sclerostin-targeting compounds [41]. Additionally, interactions with other cell types in the bone metastatic microenvironment could potentially provide new treatment options for bone metastasis [42].
One of the new options for the treatment of BoM is the transfer of gamma-delta T cells. In some studies, mice with breast cancer and BoM+, gamma-delta T cell transfer reduced tumor growth and osteolysis. Promising findings have also been demonstrated in a clinical trial [43]. Another treatment option has been to combine zoledronic acid with IL-2 therapy, which has now been tested in several metastatic tumors [44,45].
Other possible positive synergies between anti-CTLA-4 and denosumab and with anti-PD-1 and denosumab have been observed in patients with melanoma BoM+ [46,47].
While the majority of breast and prostate cancer patients with bone metastasis are treated with bone targeted therapy, currently only about 50–60% of patients with NSCLC are treated with bone-specific drugs [7,14]. This is due to the fact that, until a few years ago, the prognosis was so severe that it, unfortunately, dissuaded oncologists from prescribing BTT. With the introduction of molecular therapies—but, above all, of immunotherapy—survival has significantly increased. This change of scenario has therefore led to a conceptual shift. First, with the survival gain, the likelihood of developing bone metastasis during the course of the disease also increases. Consequently, more patients may experience SREs. As is known, SREs have a negative impact on the quality of life, so it is necessary to treat most patients with bone resorptive drugs. The second point directly concerns the greater knowledge of the close interconnection between bone marrow and the immune system. In this context, in fact, osteoimmuno-oncology has developed and has hypothesized that adequate treatment of patients with BoM+ and ICI is not only possible but is essential to guarantee them an increase in ORR, PFS, and OS. For these reasons, we believe that there is, or should be, a therapeutic shift in these patients.
The pre-clinical data reported are the result of studies on cellular interactions and pathways involved in the development of osteolytic bone metastasis mainly of breast cancer. Although there are fewer studies in NSCLC, these models are likely to be valid. It is confirmed that the RANK-RANKL pathway is the main pathway responsible for bone resorption. At the same time, more and more evidence demonstrates a close interplay between bone marrow and the immune system (Figure 1). In fact, one system regulates the other.
Therapy with immune checkpoint inhibitors fits into this context. The data available so far demonstrate that bone metastasis is an independent prognostic factor with poor outcomes in patients treated with immunotherapy. In view of the retrospective nature of the clinical data available to us, or the small prospective data, it is clear that there are modest discrepancies in the prognostic impact of ICIs and BTT in these patients. However, most of the trials indicate that the effectiveness of immunotherapy, especially when considered as monotherapy, could be modulated by the tumor and bone microenvironment.
More and more data support the idea that a hostile (cold) tumor microenvironment is created in patients with BoM+, which would reduce the effectiveness of immunotherapy. Some authors believe that the use of bone therapy, in particular bone target therapies, could reverse the resistance to immunotherapy by breaking the “vicious cycle” (Figure 1). Theoretically, an anti-RANK therapy associated with ICIs could be more synergistic. It is clear that larger prospective clinical studies are needed to confirm the hypothesis that emerged from some retrospective studies.
The clinical studies presented, in fact, have important limits due to the retrospective nature, the sample size of each single study, and the heterogeneity of patients included (first line, subsequent lines, ICI associated or not with other chemotherapeutic/antiangiogenic drugs).
The scope of the association of palliative bone radiation therapy with ICIs in BoM+ patients should also be explored with dedicated prospective studies.
Due to a “cold” TME, patients with BoM may benefit little from the combination of different types of immunotherapies, since ICIs require the presence of effector lymphocytes at the TME level to be effective. While there are drugs that allow the interruption of the “vicious cycle”, transforming the TME from “cold” to “hot” could hypothetically be more promising. For example, bisphosphonates or denosumab that inhibit osteoclast-mediated bone resorption through the inhibition of the pathway of nuclear factor kappa-B ligand receptor (RANKL) could be some of the options. Some chemotherapeutic agents are also capable of reducing immunosuppressive Tregs and inducing apoptosis of myeloid derived suppressor cells (MDSCs). Antiangiogenic drugs, normalizing vascularization, and reducing tumor hypoxia can reduce the production of immunosuppressive cytokines such as IL6, IL10, and IDO.
Thus, the combination of ICIs with chemotherapy, anti-angiogenesis, or bisphosphonates/denosumab could give therapeutic advantages to patients with BoM.
Based on new knowledge, new drug associations could be developed in the future.
Understanding osteoclast signaling in bone metastasis could help to identify new targets for drug discovery [40], and there are currently drug candidates in different phases of development that are targeting osteoclasts, such as SRC, DKK-1 (dickkopf WNT signaling pathway inhibitor 1), and Sclerostin-targeting compounds [41]. Additionally, interactions with other cell types in the bone metastatic microenvironment could potentially provide new treatment options for bone metastasis [42].
One of the new options for the treatment of BoM is the transfer of gamma-delta T cells. In some studies, mice with breast cancer and BoM+, gamma-delta T cell transfer reduced tumor growth and osteolysis. Promising findings have also been demonstrated in a clinical trial [43]. Another treatment option has been to combine zoledronic acid with IL-2 therapy, which has now been tested in several metastatic tumors [44,45].
Other possible positive synergies between anti-CTLA-4 and denosumab and with anti-PD-1 and denosumab have been observed in patients with melanoma BoM+ [46,47].
Debbie
Re: Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment …
5. Conclusions
Bone is a special immune site with a unique immunosuppressive microenvironment. Bone metastasis impairs immunotherapy efficacy, especially when used alone. Even it is not true in all the trials, bone targeted therapies appear to have a synergistic effect when used in combination with ICIs—maybe due to the interruption of the “vicious cycle”. This action probably restores a less immunosuppressive (“cold” or “hostile”) tumor and bone microenvironment. These promising outcomes have to be confirmed in larger prospective trials—even better if randomized. In view of the new therapeutic scenario of NSCLC, we believe that further studies on the significance of extracellular vesicles and on new therapeutic approaches for bone metastasis are strongly recommended.
Bone is a special immune site with a unique immunosuppressive microenvironment. Bone metastasis impairs immunotherapy efficacy, especially when used alone. Even it is not true in all the trials, bone targeted therapies appear to have a synergistic effect when used in combination with ICIs—maybe due to the interruption of the “vicious cycle”. This action probably restores a less immunosuppressive (“cold” or “hostile”) tumor and bone microenvironment. These promising outcomes have to be confirmed in larger prospective trials—even better if randomized. In view of the new therapeutic scenario of NSCLC, we believe that further studies on the significance of extracellular vesicles and on new therapeutic approaches for bone metastasis are strongly recommended.
Debbie