The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

Heymann, Marie-Françoise; Lezot, Frédéric; Heymann, Dominique

doi:10.1016/j.cellimm.2017.10.011

Cited by 176 publications

(197 citation statements)

References 126 publications

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“…The key questions to answer in this context in OS include: What is known currently about the tumor immune profile? [74][75][76] Further, expression of PD-1 on tumor infiltrating lymphocytes and its ligand PD-L1 on tumor cells has been shown both in primary OS tumors as well as lung metastases, suggesting that this pathway might play a role in tumor microenvironment. Do OS primary and/or metastatic tumors have the right milieu for immune therapies to be effective?…”

Section: Intentmentioning

confidence: 99%

“…Several studies suggest that infiltration of tumors with cytotoxic T cells as well as tumor-associated macrophages predicts improved survival in patients with OS. [74][75][76] Further, expression of PD-1 on tumor infiltrating lymphocytes and its ligand PD-L1 on tumor cells has been shown both in primary OS tumors as well as lung metastases, suggesting that this pathway might play a role in tumor microenvironment. 74,77 When compared with healthy controls, increased expression of CTLA4 on peripheral T cells and an increased ratio of immune suppressive peripheral monocytes in patients with OS may suggest a profoundly immunosuppressive environment within tumors.…”

Section: Intentmentioning

confidence: 99%

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Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

Roberts

Lizardo

Reed

et al. 2019

Cancer

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Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding. Cancer 2019;125:3514-3525.

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Section: Intentmentioning

confidence: 99%

Section: Intentmentioning

confidence: 99%

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

Roberts

Lizardo

Reed

et al. 2019

Cancer

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“…Another important challenge is the immune evasion potential of OS. As mentioned, a subgroup of OS demonstrates high expression of immune checkpoint inhibitor ligands, mainly PDL‐1 which reduces the efficacy of transferred CAR T cells . Consequently, immune checkpoint blockade although not effective as monotherapy in OS, could be valuable in combination with other treatment approaches such as CAR T‐cell therapy.…”

Section: Discussionmentioning

confidence: 99%

“…By its nature, OS has a microenvironment that favours M2 macrophages which support tumour growth and promote immune suppression. Additionally, a subset of OS has high expression of the checkpoint inhibitor ligand, PDL‐1, which plays a role in suppression of T‐cell activity through an inhibitory receptor called PD‐1 . In fact, 25% of the primary OS tumours with high PDL‐1 expression have higher likelihood of containing PD‐1 high T cells than PDL‐1 low tumours .…”

Section: Introductionmentioning

confidence: 99%

Treating osteosarcoma with CAR T cells

et al. 2019

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Novel therapies to treat patients with solid cancers that have developed resistance to chemotherapy represent unmet needs of considerable dimensions. In the present review, we will address the attempts to develop chimeric antigen receptor (CAR) targeted immunotherapy against osteosarcoma (OS). This aggressive cancer displays its peak incidence in children and young adults. The main cause of patient death is lung metastases with a 5-year survival as low as 5%-10% in the primary metastatic setting and 30% in the relapse situation, respectively. Effective adjuvant combination chemotherapy introduced more than 40 years ago improved the survival rates from below 20% to around 60% in patients; however, since then, no major breakthroughs have been made. The use of immune checkpoint inhibitors has been disappointing in OS, while other types of immunotherapies such as CAR T cells remain largely unexplored. Indeed, for CAR T-cell therapy to be efficacious, two main criteria need to be fulfilled: (a) CAR T cells should target an epitope selectively expressed on the cell surface of OS in order to prevent toxicities in normal tissues and (b) the target should also be widely expressed on OS metastases. These challenges have already been undertaken in OS and illustrate the difficulties in developing tomorrow's CAR-T treatment in a solid tumour. We will discuss the experiences with CAR-T therapy development and efficacy to combat the clinical challenges in OS.

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“…Paradoxically, there is convincing evidence that OS can be recognized by trafficking immunocytes, yet successful exploitation of immunotherapeutic strategies remains elusive. To accelerate the clinical deployment of effective antitumor immune approaches for combating OS, recent scientific investigations have focused on characterizing the quantity, phenotype, dynamics, and functional nature of immune cells that infiltrate into primary and metastatic OS lesions, and these collective findings have been recently and thoroughly summarized (223,224).…”

Section: Leveraging the Immune System To Combat Os Metastasesmentioning

confidence: 99%

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

2020

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Osteosarcoma is a malignant primary tumor of bone, arising from transformed progenitor cells with osteoblastic differentiation and osteoid production. While categorized as a rare tumor, most patients diagnosed with osteosarcoma are adolescents in their second decade of life and underscores the potential for life changing consequences in this vulnerable population. In the setting of localized disease, conventional treatment for osteosarcoma affords a cure rate approaching 70%; however, survival for patients suffering from metastatic disease remain disappointing with only 20% of individuals being alive past 5 years post-diagnosis. In patients with incurable disease, pulmonary metastases remain the leading cause for osteosarcoma-associated mortality; yet identifying new strategies for combating metastatic progression remains at a scientific and clinical impasse, with no significant advancements for the past four decades. While there is resonating clinical urgency for newer and more effective treatment options for managing osteosarcoma metastases, the discovery of druggable targets and development of innovative therapies for inhibiting metastatic progression will require a deeper and more detailed understanding of osteosarcoma metastasis biology. Toward the goal of illuminating the processes involved in cancer metastasis, a convergent science approach inclusive of diverse disciplines spanning the biology and physical science domains can offer novel and synergistic perspectives, inventive, and sophisticated model systems, and disruptive experimental approaches that can accelerate the discovery and characterization of key processes operative during metastatic progression. Through the lens of trans-disciplinary research, the field of comparative oncology is uniquely positioned to advance new discoveries in metastasis biology toward impactful clinical translation through the inclusion of pet dogs diagnosed with metastatic osteosarcoma. Given the spontaneous course of osteosarcoma development in the context of real-time tumor microenvironmental cues and immune mechanisms, pet dogs are distinctively valuable in translational modeling given their faithful recapitulation of metastatic disease

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The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

Abstract: To cite this version:

Cited by 176 publications

References 126 publications

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

Treating osteosarcoma with CAR T cells

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

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