mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

Abstract

Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) plays a crucial role in the control of cellular growth, proliferation, survival, metabolism, angiogenesis, transcription, and translation. In most human cancers, alterations to this pathway are common and cause activation of other downstream signaling pathways linked with oncogenesis. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both tumor immunity and angiogenesis. Inflammation is a hallmark of cancer, playing a central role in the tumor dynamics, and immune cells can exert antitumor functions or promote the growth of cancer cells. In this context, mTOR may regulate the activity of macrophages and T cells by regulating the expression of cytokines/chemokines, such as interleukin (IL)-10 and transforming growth factor (TGF-β), and/or membrane receptors, such as cytotoxic T-Lymphocyte protein 4 (CTLA-4) and Programmed Death 1 (PD-1). Furthermore, inhibitors of mammalian target of rapamycin are demonstrated to actively modulate osteoclastogenesis, exert antiapoptotic and pro-differentiative activities in osteoclasts, and reduce the number of lytic bone metastases, increasing bone mass in tumor-bearing mice. With regard to the many actions in which mTOR is involved, the aim of this review is to describe its role in the immune system and bone metabolism in an attempt to identify the best strategy for therapeutic opportunities in the metastatic phase of solid tumors.

Keywords: bone; everolimus; mTOR; mTOR inhibitors; metastasis; osteoimmunology; tumor immunity.

Figure 1

The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. Activation of P13K phosphorylates phosphatidylinositol 4,5-biphosphate (PIP2) to form phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 prompts the activation of downstream processes such as AKT, which transmits signals to effectors including mTOR complexes to enhance cellular processes. mTORC1 is stimulated during cell activation, whereby T-cell receptor (TCR) stimulates the activation of P13K. mTORC1 includes catalytic subunits of mTOR such as regulatory-associated protein of mTOR (RAPTOR), mammalian lethal with sec-13 protein 8 (MLST8), proline-rich Akt-substrate 40 kDa (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR). mTORC2 comprises three proteins: RICTOR, MLST8, and SIN1. Activation of mTORC2 occurs through the phosphorylation of AKT, while mTORC1, when activated, phosphorylates effectors that are major regulators of protein translation including translation-regulating factors ribosomal S6 kinase-1 (S6K-1) and eukaryote translation initiation factor 4E binding protein-1 (4EBP1) to enhance protein synthesis.

Figure 2

Immunoregulatory functions of mammalian target of rapamycin (mTOR) complexes in tumor microenvironment elements. An increase (red up-arrow) in mTORC1 activity induces Th1, Th2, and Th17 differentiation, endothelial proliferation, tumor-infiltrating regulatory T cells (Treg) differentiation in effector T cells, and M2 polarization; mTORC2 increased activity increases Th1, Th2, Th17 and M2 polarization and diminishes Treg differentiation; reduction (red down-arrow) of mTORC1 activity diminishes interleukin (IL)-6 production and CD8+ effector while increasing CD8+ memory; on the contrary, CD8+ memory is reduced if mTORC2 activity is diminished. mTOR complex 1: mTORC1. mTOR complex 2: mTORC2. Tumor-associated macrophages: TAM. Myeloid-derived suppressor cells: MDSCs. Cancer associated-fibroblasts: CAFs. < indicates a decrease in activity; > indicates an increase in activity.

Figure 3

The main consequences of mTOR inhibition on tumor, bone, and the immune system are summarized along with how vitamin D supplementation can modulate its effects and contribute to achieving a better therapeutic goal.

Figure 4

Inhibition of mTOR in cancer and bone effects: Everolimus, Vitamin D and Denosumab together contribute to inhibiting cancer progression and modulate osteoclastogenesis.