How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive

Abstract

Experimental evidence indicates that mesenchymal stromal cells (MSCs) may regulate tumor microenvironment (TME). It is conceivable that the interaction with MSC can influence neoplastic cell functional behavior, remodeling TME and generating a tumor cell niche that supports tissue neovascularization, tumor invasion and metastasization. In addition, MSC can release transforming growth factor-beta that is involved in the epithelial-mesenchymal transition of carcinoma cells; this transition is essential to give rise to aggressive tumor cells and favor cancer progression. Also, MSC can both affect the anti-tumor immune response and limit drug availability surrounding tumor cells, thus creating a sort of barrier. This mechanism, in principle, should limit tumor expansion but, on the contrary, often leads to the impairment of the immune system-mediated recognition of tumor cells. Furthermore, the cross-talk between MSC and anti-tumor lymphocytes of the innate and adaptive arms of the immune system strongly drives TME to become immunosuppressive. Indeed, MSC can trigger the generation of several types of regulatory cells which block immune response and eventually impair the elimination of tumor cells. Based on these considerations, it should be possible to favor the anti-tumor immune response acting on TME. First, we will review the molecular mechanisms involved in MSC-mediated regulation of immune response. Second, we will focus on the experimental data supporting that it is possible to convert TME from immunosuppressive to immunostimulant, specifically targeting MSC.

Keywords: carcinoma-associated fibroblast; immunosuppression; mesenchymal stromal cells; tumor microenvironment; tumor-associated fibroblast.

Figure 1

Mesenchymal stromal cell (MSC) plasticity. MSCs are present in every tissue, where they represent a key component characterized by the ability to differentiate into several types of mesodermal cells, including osteocytes, adipocytes, chondrocytes, endothelial cells, pericytes, and fibroblasts (red arrows). It is not clear whether all these kinds of cells can in turn de-differentiate back to MSC (green dotted arrows). The function of these cells is to maintain the homeostasis of the tissue/organ where they are present, regulating the production of the extracellular matrix components. Upon stimulation with physical, chemical, or biological stimuli, they participate in the reconstitution of the equilibrium among cellular and matrix components of a given tissue, leading to damage repair. They can be considered as sensor of the tissue conditions which can coordinate the molecular mechanisms that maintain tissue integrity. Upon influence of microenvironment, fibroblasts can lead to tumor-associated/carcinoma-associated fibroblasts (TAF/CAF), activated fibroblast and fibroblast involved in repair of the tissue.

Figure 2

Functional behavior of mesenchymal stromal cells (MSCs) interacting with cells of the immune system. MSCs display several functional abilities during the interaction with cell of the immune system. Resting leukocytes are typically supported by MSC through direct cell-to-cell contact involving different types of receptor on the leukocyte membrane and the corresponding ligands expressed on MSC or on differentiated MSC. Some soluble factors and interleukins are also involved, such as stromal-derived factor 1, IL-6, and IL-15. Due to this interaction, leukocytes receive an anti-apoptotic signal which leads to their survival (A). This effect is also involved in the maintenance of the neoplastic counterpart of T, B lymphocytes and myeloid cells. After signals inducing proliferation, cytokine release, or activation of cytolytic machinery, MSCs exert a potent inhibitory effect that reduces leukocyte proliferation and effector functions (B). In addition, activated MSCs interfere with the differentiation of monocytes to immature DC (iDC) or mature DC (mDC), thus blocking the generation of professional antigen-presenting cells (APC) (C). The release via microvescicles, exosomes or in soluble form, of decoy molecules such as HLA-I, ligands for NKG2D or other activating receptors involved in tumor cell recognition and killing, hampers the anti-tumor activity of T and NK lymphocytes (D). Furthermore, MSC can release TGF-β, sheddases, such as metalloproteinases, and a disintegrin and metalloproteinase members, which can induce the release of decoy receptors from MSC, tumor cells, and bystander cells in the microenvironment. TGF-β can inhibit tumor cell recognition reducing the activation-induced increase of NKG2D expression on anti-tumor effector lymphocytes (D). All these events eventually lead to the impairment of both innate and adaptive immune responses.

Figure 3

Means to enhance the immune response in the tumor microenvironment (TME). To counteract the mesenchymal stromal cell (MSC)-mediated downregulation of immune response, two main approaches can be utilized: (A) blocking of immunosuppressive effect; (B) triggering MSC to be immunostimulant rather than immunosuppressive. (A) MSC can downregulate immune response through several soluble factors such as indoleamine 2,3 dioxygenase (IDO) prostaglandin E₂ and TGF-β. In turn, TGF-β from MSC, tumor cells, and bystander cells in TME can support tumor cell growth and dissemination. This latter event is linked to epithelial–mesenchymal transition (EMT) that triggers the generation of metastasis. The blockade of MSC immunosuppression can be obtained by several means: (a) drugs that inhibit the activity or the generation of molecules involved in immunosuppression such as inhibitors of IDO, HO, TGF-β, hepatocyte growth factor (HGF), PGE₂, NOS, and ARGI–II; (b) antibodies directed either to MSC growth receptors, as the epidermal growth factor and platelet-derived growth factor (PDGF) or to the fibroblast activation protein (FAP). It is of note that some of these receptors are shared by tumor cells; thus, human or humanized antibodies-based therapy can target both MSC and cancer cells. These antibodies act inhibiting the effect of a given growth factor but also impairing the function of the target molecule. In addition, they trigger complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) elicited by Fcγ receptor-expressing cells, including natural killer (NK) cells and γδ T cells. These antibodies can be a portion of antibody–drug conjugates (ADC), which join the antibody-mediated effect to that of a cytotoxic drug, leading to a strong inhibition of tumor cell growth or MSC-mediated functions. (c) cytotoxic T cells equipped with chimeric antigen receptors (CARs) specific for FAP (FAP-CAR T cells) that can recognize FAP⁺ cells; (d) drugs affecting the mevalonate pathway that is essential for both MSC and tumor cell metabolism; unfortunately, mevalonate is relevant also for the development of an optimal immune response; they should therefore be used carefully; (e) inhibitors of sheddases, as matrix metalloproteinase and a disintegrin and metalloproteinases, which can inhibit tumor cell growth limiting the generation of growth factors in a suitable form to trigger proliferation; furthermore, these inhibitors should impair the generation of decoy molecules, reducing the competition between membrane and soluble ligands for activating receptors on effector lymphocytes; (f) tyrosine kinase inhibitors (TKi) which block the activity of MSC besides hindering tumor cell growth. (B) Immunomodulatory drugs (IMiDs), among which thalidomide, pomalidomide, lenalidomide, and avadomide can trigger the innate and the adaptive immune responses, besides hampering angiogenesis in the tumor. Aminobiphosphonates (N-BPs), such as zoledronic acid, can interfere with the mevalonate pathway strongly enhancing the production of isopentenyl pyrophosphate (IPP) and dimethyl allyl pyrophosphate (DMPP). These small pyrophosphates can trigger the expansion of γδ T cells of the Vδ2 subset, a cell population with potent anti-tumoral capabilities. Furthermore, Vδ2⁺ T cells express the FcγR involved in ADCC, reinforcing the anti-tumor effect of human/humanized antibodies.