Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells

Cell Mol Life Sci. 2022 Sep 12;79(10):513. doi: 10.1007/s00018-022-04524-7.

Abstract

The link between cancer and aberrant glycosylation has recently become evident. Glycans and their altered forms, known as tumour-associated carbohydrate antigens (TACAs), are diverse, complex and difficult to target therapeutically. Lectins are naturally occurring glycan-binding proteins that offer a unique opportunity to recognise TACAs. T cells expressing chimeric antigen receptors (CARs) have proven to be a successful immunotherapy against leukaemias, but so far have shown limited success in solid tumours. We developed a panel of lectin-CARs that recognise the glycosphingolipid globotriaosylceramide (Gb3), which is overexpressed in various cancers, such as Burkitt's lymphoma, colorectal, breast and pancreatic. We have selected the following lectins: Shiga toxin's B-subunit from Shigella dysenteriae, LecA from Pseudomonas aeruginosa, and the engineered lectin Mitsuba from Mytilus galloprovincialis as antigen-binding domains and fused them to a well-known second-generation CAR. The Gb3-binding lectin-CARs have demonstrated target-specific cytotoxicity against Burkitt's lymphoma-derived cell lines as well as solid tumour cells from colorectal and triple-negative breast cancer. Our findings reveal the big potential of lectin-based CARs as therapeutical applications to target Gb3 and other TACAs expressed in haematological malignancies and solid tumours.

Keywords: CAR T cells; Cancer; Carbohydrates Immunotherapy Aberrant glycans; Cell death; Gb3; Globotriaosylceramide; Glycans; Glycosphingolipid targeting; Killing; Lectin; Tumour-associated carbohydrate antigens.

MeSH terms

  • Burkitt Lymphoma* / metabolism
  • Burkitt Lymphoma* / therapy
  • Colorectal Neoplasms*
  • Humans
  • Lectins / metabolism
  • Polysaccharides / metabolism
  • Receptors, Chimeric Antigen*
  • T-Lymphocytes

Substances

  • Lectins
  • Polysaccharides
  • Receptors, Chimeric Antigen