Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

Abstract

Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20-40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for neuroblastoma treatment, these immune escape mechanisms restrain clinical results. Therefore, we aimed to improve neuroblastoma immunogenicity to further the development of antigenspecific immunotherapy against neuroblastoma. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells which thereby readily sensitize neuroblastoma cells for recognition by CTLs. We show that oncoprotein PRAME serves as an immunodominant antigen for neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAME SLLQHLIGL /A2-specific CTL clones. Furthermore, NK cells induce MHC I upregulation in neuroblastoma through contact-dependent secretion of IFNγ. Our results demonstrate remarkable plasticity in the peptide/MHC I surface expression of neuroblastoma cells, which is reversed when neuroblastoma cells experience innate immune attack by sensitized NK cells. These findings support the exploration of NK cells as adjuvant therapy to enforce neuroblastoma-specific CTL responses.

PRAME expression and promoter hypomethylation in epithelial ovarian cancer

“…However, one caveat is that only for PRAME microarray data did this effect reach statistical significance, while RNAseq did not. A possible explanation for the improved survival seen with PRAME mRNA expression is that PRAME may be immunogenic in EOC patients, and this immunogenicity could drive reduced disease burden [6, 10, 21]. This hypothesis should be tested using studies of PRAME specific antibodies and T-cell responses, and by determining their relationship to patient survival.…”

“…PRAME is an autosomal cancer-testis antigen (CTA) gene, based on its chromosomal location, expression profile, and immunogenicity. PRAME is not commonly expressed in normal adult somatic tissues, with the exception of testis [6], but is expressed in many cancers, and is immunogenic [8–10]. PRAME is expressed in both solid tumors and leukemia, making it an attractive potential immunotherapy target [11].…”

Systematic identification of cancer-specific MHC-binding peptides with RAVEN

“…Among them we found not only many established CSGs such as LIPI for Ewing sarcoma, 21 PRAME for neuroblastoma 22,23 and members of the MAGE -family for germinoma, 24 neuroblastoma, 25 synovial sarcoma, 26 multiple myeloma, 27 diffuse large B cell lymphoma (DLBCL), 28 and osteosarcoma, 29 but also many novel candidates of which some appear to be suitable for targeting multiple cancer entities (Figure 2, Supplementary Table 5, Supplementary Figure 1).

10.1080/2162402X.2018.1481558-F0002Figure 2.Overexpressed CSGs in multiple cancer entities identified with RAVEN.

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Synergistic anti‐pancreatic cancer immunological effects by treatment with reduced expression in immortalized cells/dickkopf‐3 protein and peripheral blood mononuclear cells

“…This result indicates that the REIC/DKK3 protein induced therapeutic effects against cancer cells by activating PBMC lymphocytes. It is uncertain why there are varying effects among different cell lines, but we expect that immunogenicity varies somewhat among cell lines . Additionally, as PBMCs contain about up to 30% NK cells, unstimulated PBMCs have a cytotoxic effect .…”

“…It is uncertain why there are varying effects among different cell lines, but we expect that immunogenicity varies somewhat among cell lines. 22 Additionally, as PBMCs contain about up to 30% NK cells, 23 unstimulated PBMCs have a cytotoxic effect. 24,25 We think that the sensitivity of pancreatic cancer cells toward NK cells varies among the cell lines.…”