Background Cancers affect a large number of people worldwide and sometimes have mortality rates of over 90% (pancreatic ductal adenocarcinoma (PDAC), high grade glioblastomas). Currently, immunotherapeutic strategies fail in number of cancer cases due to a lack of understanding of the molecular mechanisms operated by these cancers to evade immune surveillance. Recent evidence demonstrated that the protein galectin-9 is highly expressed in majority of cancer cells. Importantly, this protein is a crucial part of the immune evasion machinery operated by human malignant tumours. Understanding the biochemistry of this immune evasion machinery is required for designing highly efficient and affordable personalised targeted immunotherapy of human cancers.
Materials and Methods We used, glioblastoma, PDAC, breast and renal cancer cell lines as cancer cell models. Jurkat T lymphocytes, TALL-104 cytotoxic T cells and primary human and mouse CD3-positive T lymphocytes were employed for immune evasion studies. C57 BL16 mice were used for in vivo studies. Western blot analysis, on-cell and in-cell Western, ELISA, qRT-PCR, chromatin immunoprecipitation (ChIP) assays as well as a variety of biochemical tests were used to conduct the studies.
Results We found that T cells trigger galectin-9 expression and secretion (in most cases requires Tim-3 protein (T cell immunoglobulin and mucine domain containing protein 3)) in a variety of human cancer cells including but not limited to glioblastoma, PDAC, breast and renal cancers. Galectin-9 triggers exhaustion and often death of cytotoxic T cells. Other immune checkpoint proteins including VISTA (V-domain Ig-containing suppressor of T cell activation) and PD-L1 (ligand of programmed cell death protein 1) promote apoptotic death of cytotoxic T cells induced by galectin-9. Activity of T helpers, required to induce cytotoxic T lymphocytes is also suppressed by galectin-9 in cooperation with VISTA and PD-L1. We discovered that expression of all these immune checkpoint proteins is differentially controlled by the autocrine transforming growth factor beta type 1 (TGF-β)-Smad3 pathway as well as several types of interferons.
Conclusions The immune evasion machinery triggered by TGF-β-Smad3 and interferon pathways and operated by galectin-9, Tim-3, VISTA and PD-L1 should be considered as a potential target for personalised immunotherapy of cancer. Importantly, blood and tumour sample tests could help mapping the exact immune evasion networks employed by each tumour and the pathways responsible to produce respective immune checkpoint proteins. As such, personalised targeted immunotherapy could be adapted. Further investigations required to map the immune evasion machinery for each type of cancer and design the best targets for personalised immunotherapy of human malignancies.
Disclosure Information V.V. Sumbayev: None. I. Yasinska: None. S. Schlichtner: None. G.S. Lall: None. E. Fasler-Kan: None. B.F. Gibbs: None.
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