Various checkpoint molecules, and tumor-infiltrating lymphocytes in common pediatric solid tumors: Possibilities for novel immunotherapy

Mochizuki, Kazuhiro; Kawana, Satoshi; Yamada, Shuhei; Muramatsu, Moe; Sano, Hideki; Kobayashi, Shogo; Ohara, Yoshihiro; Takahashi, Nobuhisa; Hakozaki, Michiyuki; Yamada, Hitoshi; Hashimoto, Yuko; Kikuta, Atsushi

doi:10.1080/08880018.2019.1578843

Cited by 28 publications

(37 citation statements)

References 37 publications

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“…We cannot rule out that this decrease is due to migration of NK cells from the periphery into tumors, however, arguments against this are: i) there is no difference in the proportion of NK cells in the periphery expressing the CXCR3 receptor essential for tumor entry and ii) pediatric tumors generally contain few immune cells 51 . An alternative explanation, given that the lifespan of NK cells is only two weeks, is that NK cell homeostasis is disturbed.…”

Section: Discussionmentioning

confidence: 98%

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

Syrimi

Khan

Murray

et al. 2020

Preprint

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Syrimi et al. High-Dimensional mass cytometry analysis reveals systemic immune perturbations in paediatric cancer influenced by ageOne Sentence Summary: High dimensional analysis of systemic immunity in pediatric cancer patients reveals clinically relevant immune changes in NK and T-cells that vary with patient age. Abstract:Systemic immunity plays important roles in cancer immune surveillance and therapy but little is known about the immune status of healthy children or children with cancer. We performed a high dimensional single cell analysis of systemic immunity in pediatric cancer patients and agematched healthy children. In young children with cancer (age <8years) NK cells were decreased in frequency, maturity, expression of perforin and granzyme-B, and were less cytotoxic in ex vivo assays. NK cell activity was restored after in vitro culture with interleukin-2. In contrast, older children with cancer (>8 years old) had decreased naive CD4 and CD8 T-cells with concomitant increases in effector memory and T effector memory RA-revertant (TEMRA) Tcells. These immunological changes in pediatric cancer patients are relevant to the better understanding of how cancers diagnosed in childhood interact with systemic immunity and could inform the development and application of effective immune-modulating therapies in the pediatric population. Syrimi et al. High-Dimensional mass cytometry analysis reveals systemic immune perturbations in paediatric cancer influenced by age

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Section: Discussionmentioning

confidence: 98%

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

Syrimi

Khan

Murray

et al. 2020

Preprint

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“…APC presents exogenous peptides or endogenous peptides to helper T cells by binding MHC-II to peptides, and thus informs that the body is being invaded [ 57 ]. Previous studies have shown that osteosarcoma cells can express moderate to high levels of Herpes virus entry mediator on the tumor [ 58 ], and osteosarcoma cells can be killed and phagocytosed by Killer Dendritic Cells [ 59 ]. Therefore, during the process of malignant transformation, osteosarcoma cells express some antigenic substances, which are recognized by APC and presented to helper T cells via MHC-II.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential crucial genes and key pathways in osteosarcoma

Liu

Xie

et al. 2020

Hereditas

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Background The aim of this study is to identify the potential pathogenic and metastasis-related differentially expressed genes (DEGs) in osteosarcoma through bioinformatic analysis of Gene Expression Omnibus (GEO) database. Results Gene expression profiles of GSE14359, GSE16088, and GSE33383, in total 112 osteosarcoma tissue samples and 7 osteoblasts, were analyzed. Seventy-four normal-primary DEGs (NPDEGs) and 764 primary-metastatic DEGs (PMDEGs) were screened. VAMP8, A2M, HLA-DRA, SPARCL1, HLA-DQA1, APOC1 and AQP1 were identified continuously upregulating during the oncogenesis and metastasis of osteosarcoma. The enriched functions and pathways of NPDEGs include procession and presentation of antigens, activation of MHC class II receptors and phagocytosis. The enriched functions and pathways of PMDEGs include mitotic nuclear division, cell adhesion molecules (CAMs) and focal adhesion. With protein-protein interaction (PPI) network analyzed by Molecular Complex Detection (MCODE) plug-in of Cytoscape software, one hub NPDEG (HLA-DRA) and 7 hub PMDEGs (CDK1, CDK20, CCNB1, MTIF2, MRPS7, VEGFA and EGF) were eventually selected, and the most significant pathways in NPDEGs module and PMDEGs module were enriched in the procession and presentation of exogenous peptide antigen via MHC class II and the nuclear division, respectively. Conclusions By integrated bioinformatic analysis, numerous DEGs related to osteosarcoma were screened, and the hub DEGs identified in this study are possibly part of the potential biomarkers for osteosarcoma. However, further experimental studies are still necessary to elucidate the biological function and mechanism of these genes.

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“…In contrast to adult tumor entities, little is known about tumorinfiltrating lymphocytes in pediatric, solid tumor entities. Most pediatric studies in context of TILs focused on the infiltration of conventional T cells (15,(17)(18)(19)36), whereas infiltration of γδ T cells is described in pediatric medulloblastoma (14) and of iNKT cells is described in neuroblastoma (16,31). To date and to our knowledge, there is no data available that investigates infiltrating lymphocytes in pediatric PRCC.…”

Section: Discussionmentioning

confidence: 99%

Tumor Lipids of Pediatric Papillary Renal Cell Carcinoma Stimulate Unconventional T Cells

et al. 2020

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Papillary renal cell carcinoma (PRCC) is a rare entity in children with no established therapy protocols for advanced diseases. Immunotherapy is emerging as an important therapeutic tool for childhood cancer. Tumor cells can be recognized and killed by conventional and unconventional T cells. Unconventional T cells are able to recognize lipid antigens presented via CD1 molecules independently from major histocompatibility complex, which offers new alternatives for cancer immunotherapies. The nature of those lipids is largely unknown and α-galactosylceramide is currently used as a synthetic model antigen. In this work, we analyzed infiltrating lymphocytes of two pediatric PRCCs using flow cytometry, immunohistochemistry and qRT-PCR. Moreover, we analyzed the CD1d expression within both tumors. Tumor lipids of PRCC samples and three normal kidney samples were fractionated and the recognition of tumor own lipid fractions by unconventional T cells was analyzed in an in vitro assay. We identified infiltrating lymphocytes including γδ T cells and iNKT cells, as well as CD1d expression in both samples. One lipid fraction, containing ceramides and monoacylglycerides amongst others, was able to induce the proliferation of iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy donors and of one matched PRCC patient. Furthermore, CD1d tetramer stainings revealed that a subset of iNKT cells is able to bind lipids being present in fraction 2 via CD1d. We conclude that PRCCs are infiltrated by conventional and unconventional T cells and express CD1d. Moreover, certain lipids, present in pediatric PRCC, are able to stimulate unconventional T cells. Manipulating these lipids and T cells may open new strategies for therapy of pediatric PRCCs.

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Various checkpoint molecules, and tumor-infiltrating lymphocytes in common pediatric solid tumors: Possibilities for novel immunotherapy

Cited by 28 publications

References 37 publications

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

Identification of potential crucial genes and key pathways in osteosarcoma

Tumor Lipids of Pediatric Papillary Renal Cell Carcinoma Stimulate Unconventional T Cells

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