Tumor-associated disialylated glycosphingolipid antigen-revealing antibodies found in melanoma patients' immunoglobulin repertoire suggest a two-direction regulation mechanism between immune B cells and the tumor

Beatrix Kotlan, Szabolcs Horvath, Klara Eles, Vanda K. Plotar, Gyorgy Naszados, Katalin Czirbesz, Miri Blank, Emil Farkas, Laszlo Toth, Jozsef Tovari, Andras Szekacs, Yehuda Shoenfeld, Maria Godeny, Miklos Kasler, Gabriella Liszkay

Research output: Contribution to journalArticle

Abstract

There is far less information available about the tumor infiltrating B (TIL-B) cells, than about the tumor infiltrating T cells. We focused on discovering the features and potential role of B lymphocytes in solid tumors. Our project aimed to develop innovative strategies to define cancer membrane structures. We chose two solid tumor types, with variable to considerable B cell infiltration. The strategy we set up with invasive breast carcinoma, showing medullary features, has been introduced and standardized in metastatic melanoma. After detecting B lymphocytes by immunohistochemistry, VH-JH, Vκ-Jκ immunoglobulin rearranged V region genes were amplified by RT-PCR, from TIL-B cDNA. Immunoglobulin variable-region genes of interest were cloned, sequenced, and subjected to a comparative DNA analysis. Single-chain variable (scFv) antibody construction was performed in selected cases to generate a scFv library and to test tumor binding capacity. DNA sequence analysis revealed an overrepresented VH3-1 cluster, represented both in the breast cancer and the melanoma TIL-B immunoglobulin repertoire. We observed that our previously defined anti GD3 ganglioside-binder antibody-variable region genes were present in melanoma as well. Our antibody fragments showed binding potential to disialylated glycosphingolipids (GD3 ganglioside) and their O acetylated forms on melanoma cancer cells. We conclude that our results have a considerable tumor immunological impact, as they reveal the power of TIL-B cells to recognize strong tumor-associated glycosphingolipid structures on melanomas and other solid tumors. As tumor-derived gangliosides affect immune cell functions and reduce the B lymphocytes' antibody production, we suspect an important B lymphocyte and cancer cell crosstalk mechanism. We not only described the isolation and specificity testing of the tumor infiltrating B cells, but also showed the TIL-B cells' highly tumor-associated GD3 ganglioside-revealing potential in melanomas. The present data help to identify new cancer-associated biomarkers that may serve for novel cancer diagnostics. The two-direction regulation mechanism between immune B cells and the tumor could eventually be developed into an innovative cancer treatment strategy.

Original languageEnglish
Article number650
JournalFrontiers in immunology
Volume10
Issue numberAPR
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • B lymphocytes
  • Glycosphingolipids (GSLs)
  • Immune regulation
  • Immunoglobulin
  • Metastatic melanomas
  • Natural antibody
  • Tumor-associated antigen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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