Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D–NKG2DL dependent manner

Fernández, Lucía; Valentín, Jaime; Zalacaín, Marta; Leung, Wing; Patiño-García, Ana; Pérez‐Martínez, Antonio

doi:10.1016/j.canlet.2015.07.042

Cited by 63 publications

(61 citation statements)

References 42 publications

(48 reference statements)

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“…Second, identifying the rare patients with a negative or weak expression of HLA class I molecules on primary tumour is of clinical interest, to consider a different therapeutic approach (i.e. strategy based on NK cells) [31]. …”

Section: Discussionmentioning

confidence: 99%

Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy

Sundara

Kostine

Cleven

et al. 2016

Cancer Immunol Immunother

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IntroductionImmunotherapy may be an excellent choice for treating osteosarcoma given its exceptionally high genomic instability, potentially generating neoantigens. In this study, we aim to investigate the HLA class I expression, PD-L1 and tumour-infiltrating lymphocytes in primary osteosarcomas and relapses/metastases, as well as their changes during disease progression.Materials and methodsTumour samples from multiple stages of the disease (pretreatment biopsies, surgical resections of primary osteosarcomas, relapses and metastases) were collected and stained for HLA-A (HCA2), HLA-B/C (HC10), β2-microglobulin and PD-L1 using immunohistochemistry on whole sections. Density and type of T-cell infiltrate were characterised by a triple immunofluorescent staining CD3-CD8-FOXP3.ResultsOverall, 85 formalin-fixed, paraffin-embedded blocks from 25 osteosarcoma patients were included. HLA class I expression was detected in 94% of osteosarcomas (strongly positive in 56%, heterogeneous in 38%) and negative or weakly positive in 6%, without differences between the stages of the disease. HLA-A expression was more frequently negative than HLA-B/C. Tumour-infiltrating lymphocytes were highly heterogeneous and mainly observed in tumour areas with expression of HLA class I. Density of T cells was significantly higher in metastases than in primary tumours and local relapses (p = 0.0003). Positive PD-L1 expression was found in 13% of primary tumours, 25% of relapses and 48% of metastases and correlated with a high T-cell infiltrate (p = 0.002).ConclusionAn increased number of tumour-infiltrating T cells and PD-L1 expression in metastases compared with primary tumours, suggesting accessibility for T cells, could imply that osteosarcoma patients with metastatic disease may benefit from T-cell-based immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1925-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy

Sundara

Kostine

Cleven

et al. 2016

Cancer Immunol Immunother

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“…Numerous immunotherapies were assessed to modulate the tumor microenvironment and to reactivate a prolonged and efficient immune response [6]. Adoptive cell therapies based on TIL as described above and generating antigen-specific lymphocytes [103][104][105], dendritic cells [106][107][108][109][110][111][112], NK cells [113][114][115][116][117][118] were developed mostly in vitro and in pre-clinical model of osteosarcoma. Several clinical trials are currently in progress for evaluating their therapeutic efficacy in patients (Table 1).…”

Section: Lymphocytes Subpopulations In Osteosarcoma and Therapeutic Imentioning

confidence: 99%

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

Heymann

Lezot

Heymann

2019

Cellular Immunology

164

183

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“…Recently, other studies demonstrated altered levels of immune cells which were linked to success of therapy against osteosarcoma. For instance, an increase in CD8 + T cells [43] or increases in NK cells [44], [45] seemed to be mediators of successful immunotherapy against osteosarcoma and metastases thereof. Likewise, our study demonstrated an increase of CD4 + , CD8 + , and NK cells in the lung parenchyma after F8-TNF treatment, which may provide an explanation for the reduced numbers of early pulmonary metastases.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of F8-TNF-α in Models of Early and Progressive Metastatic Osteosarcoma

Robl

Botter

Boro

et al. 2017

Translational Oncology

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The targeted delivery of tumor necrosis factor-α (TNF-α) with antibodies specific to splice isoforms of fibronectin [e.g., F8-TNF, specific to the extra-domain A (EDA) domain of fibronectin] has already shown efficacy against experimental sarcomas but has not yet been investigated in orthotopic sarcomas. Here, we investigated F8-TNF in a syngeneic K7 M2–derived orthotopic model of osteosarcoma as a treatment against pulmonary metastases, the most frequent cause of osteosarcoma-related death. Immunofluorescence on human osteosarcoma tissue confirmed the presence of EDA in primary tumors (PTs) as well as metastases. In mice, the efficacy of F8-TNF against PTs and early pulmonary metastases was evaluated. Intratibial PT growth was not affected by F8-TNF, yet early micrometastases were reduced possibly due to an F8-TNF–dependent attraction of pulmonary CD4+, CD8+, and natural killer cells. Furthermore, immunofluorescence revealed stronger expression of EDA in early pulmonary metastases compared with PT tissue. To study progressing pulmonary metastases, a hind limb amputation model was established, and the efficacy of F8-TNF, alone or combined with doxorubicin, was investigated. Despite the presence of EDA in metastases, no inhibition of progressive metastatic growth was detected. No significant differences in numbers of CD4+ or CD8+ cells or F4/80+ and Ly6G+ myeloid-derived cells were observed, although a strong association between metastatic growth and presence of pulmonary Ly6G+ myeloid-derived cells was detected. In summary, these findings demonstrate the potential of F8-TNF in activating the immune system and reducing early metastatic growth yet suggest a lack of efficacy of F8-TNF alone or combined with doxorubicin against progressing osteosarcoma metastases.

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Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D–NKG2DL dependent manner

Cited by 63 publications

References 42 publications

Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy

Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy

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

Evaluation of F8-TNF-α in Models of Early and Progressive Metastatic Osteosarcoma

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