The Immune Landscape of Osteosarcoma: Implications for Prognosis and Treatment Response
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cells Review The Immune Landscape of Osteosarcoma: Implications for Prognosis and Treatment Response Caterina Cascini and Claudia Chiodoni * Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-022-390-2212 Abstract: Osteosarcoma (OS) is a high-grade malignant stromal tumor composed of mesenchymal cells producing osteoid and immature bone, with a peak of incidence in the second decade of life. Hence, although relatively rare, the social impact of this neoplasm is particularly relevant. Differently from carcinomas, molecular genetics and the role of the tumor microenvironment in the development and progression of OS are mainly unknown. Indeed, while the tumor microenvironment has been widely studied in other solid tumor types and its contribution to tumor progression has been definitely established, tumor–stroma interaction in OS has been quite neglected for years. Only recently have new insights been gained, also thanks to the availability of new technologies and bioinformatics tools. A better understanding of the cross-talk between the bone microenvironment, including immune and stromal cells, and OS will be key not only for a deeper knowledge of osteosarcoma pathophysiology, but also for the development of novel therapeutic strategies. In this review, we summarize the current knowledge about the tumor microenvironment in OS, mainly focusing on immune cells, discussing their role and implication for disease prognosis and treatment response. Keywords: osteosarcoma; tumor microenvironment; macrophages; bone marrow; osteoclasts; mes- Citation: Cascini, C.; Chiodoni, C. enchymal stem cells The Immune Landscape of Osteosarcoma: Implications for Prognosis and Treatment Response. Cells 2021, 10, 1668. https:// 1. Introduction doi.org/10.3390/cells10071668 Osteosarcoma (OS), the most frequent bone tumor in children and adolescents, is a Academic Editor: Annalisa Santucci high-grade malignancy characterized by the formation of an osteoid matrix and imma- ture bone, mainly in the metaphysis and diaphysis of long bones [1]. OS shows a very Received: 14 May 2021 aggressive behavior with lung micro-metastases often already present at the time of di- Accepted: 29 June 2021 agnosis. Although primary lesions can be efficiently treated with surgical resection and Published: 2 July 2021 (neo)adjuvant chemotherapy administration (doxorubicin, cisplatin, methotrexate, and ifosfamide), no effective treatment options are yet available for metastatic OS [2]. Indeed, Publisher’s Note: MDPI stays neutral whereas the five-year survival rate is more than 78% for localized disease, it drops to 25% with regard to jurisdictional claims in for metastatic or relapsing OS [3]. published maps and institutional affil- Although the precise cell of origin for OS is still unclear, some evidence indicates iations. that it could arise from mesenchymal stem cells (MSCs) or from osteoblastic progenitors unable to proceed to terminal differentiation [4]. In the putative cell of origin, many genetic alterations, such as copy number variants and multiple fusion sequences in chromosomes, occur with high frequency and draw a complex genetic scenario that hinders the identifica- Copyright: © 2021 by the authors. tion of a unique driver mutation for further therapeutic strategies [5]. OS aggressiveness Licensee MDPI, Basel, Switzerland. and poor prognosis for metastatic patients, together with the absence of targeted therapies, This article is an open access article make it urgent to identify new therapeutic approaches to improve the overall survival rate distributed under the terms and of OS patients. conditions of the Creative Commons In the search for new therapeutic targets, in recent decades, the tumor microenviron- Attribution (CC BY) license (https:// ment (TME) has gained increasing attention in several tumor types. However, differently creativecommons.org/licenses/by/ from most carcinomas, a clear picture of the TME and of its role in the development and 4.0/). Cells 2021, 10, 1668. https://doi.org/10.3390/cells10071668 https://www.mdpi.com/journal/cells Cells 2021, 10, 1668 2 of 13 Cells 2021, 10, x 2 of 14 progression of OS is still lacking. Indeed, while it has been widely studied in other solid tumor types and its contribution to tumor progression has definitely been established [6,7], tumor–stromaronment (TME) interaction has gained in increasing OS has been attention quite in neglectedseveral tumor thus types. far andHowever, the few dif- available findingsferently are from sometimes most carcinomas, contradictory a clear withpicture other of the tumor TME and types. of its In role addition, in the devel- bone marrow (BM)opment is a very and specializedprogression of microenvironment, OS is still lacking. Indeed, containing while it highlyhas been heterogeneous widely studied in cell types, other solid tumor types and its contribution to tumor progression has definitely been rangingestablished from hematopoietic[6,7], tumor–stroma cells interaction to mesenchymal, in OS has vascular,been quite andneglected neuronal thus far cells. and However, in thethe last few few available years, findings also thanks are sometimes to recent contradictory technological with advances,other tumor new types. insights In addi- in the OS TMEtion, have bone been marrow gained. (BM) This is a very review specializ triesed to microenvironment, summarize thestate containing of the highly art of het- the TME in OS, witherogeneous a particular cell types, focus ranging on tumor-infiltratingfrom hematopoietic cells immune to mesenchymal, cells and their vascular, correlation and with patients’neuronal prognosis cells. However, and response in the last to treatment.few years, also thanks to recent technological ad- vances, new insights in the OS TME have been gained. This review tries to summarize the 2. Thestate Heterogenous of the art of the Bone TME Marrowin OS, with Microenvironment a particular focus on tumor-infiltrating immune cells and their correlation with patients’ prognosis and response to treatment. Differently from other primary tumors, the tumor microenvironment of OS is the BM, a highly2. The dynamic Heterogenous environment Bone Marrow composed Microenvironment of bone cells, immune cells, and stromal and vascularDifferently cells, embedded from other in primary a mineralized tumors, extracellularthe tumor microenvironment matrix. In normal of OS is physiological the conditions,BM, a highly all these dynamic cell environment types act incomposed coordination of bone tocells, maintain immune bonecells, and stromal hematopoietic homeostasis.and vascular The cells, cross-talk embedded between in a mineralized these cell extracellula types isr matrix. tightly In regulated normal physio- by cytokines andlogical growth conditions, factors, whichall these are cell also types responsible act in coordination for bone to maintain remodeling bone throughand hemato- the balance betweenpoietic the homeostasis. activities The of osteoclastscross-talk between and osteoblasts. these cell types The is tightly concept regulated that the by immunecyto- cells kines and growth factors, which are also responsible for bone remodeling through the andbalance bone tissue between are the strictly activities interconnected of osteoclasts hasand recentlyosteoblasts. led The to concept the development that the im- of a new interdisciplinarymune cells and field, bone “osteoimmunology”tissue are strictly interconnected [8]. While has the recently original led idea to the was develop- mainly focused on thement role of ofa new immune interdisciplinary cells in bone field, damage “osteoimmunology” in pathological [8]. conditions,While the original such asidea inflamma- torywas diseases mainly or focused neoplastic on the malignancies,role of immune accumulatingcells in bone damage evidence in pathological has demonstrated condi- that bonetions, cells such can as also inflammatory reciprocally diseases regulate or neoplastic immune malignancies, cells and hematopoiesis. accumulating evidence In this context, it fitshas well demonstrated the idea thatthat thebone pathophysiology cells can also reciprocally of OS regulate is strictly immune dependent cells and not hema- only on the topoiesis. In this context, it fits well the idea that the pathophysiology of OS is strictly molecular events underlining osteoblast differentiation, but also on the interaction with dependent not only on the molecular events underlining osteoblast differentiation, but the otheralso on cell the typesinteraction residing with the in theother BM cell [ 9types] (Figure residing1). in the BM [9] (Figure 1). Figure 1. The complex osteosarcoma microenvironment in the bone tissue. Osteosarcoma (OS) develops in the highly Figure 1. The complex osteosarcoma microenvironment in the bone tissue. Osteosarcoma (OS) develops in the highly specialized bone marrow (BM) environment, a highly dynamic tissue composed of bone cells, immune cells, and stromal specializedand bone vascular marrow cells, embedded (BM) environment, in a mineralized a highly extracellular dynamic ma tissuetrix. The composed different cell of bonetypes cells,are reciprocally immune regulated, cells, and stromal and vascularwith OS cells, cells embedded producing factors in a mineralizedthat recruit and extracellular re-program immune, matrix. stromal, The different and bone cells cell to types their areadvantage,