An in vitro model for immunomodulation in melanoma
Hematology, Oncology
Immunology
Cell Biology
Final Report Abstract
Numerous studies over the years, including our own, have consistently implicated the tumour microenvironment and in particular so-called myeloid-derived suppressor cells (MDCSC) in tumour escape from the immune response. It is even possible to track MDSCs in the blood and extract important prognostic and predictive information regarding patient clinical outcome under immunotherapy. Understanding the reasons for the generation of MDSC by the tumour and how to circumvent this thus has important clinical ramifications, and not only for immunotherapies. However, investigations of tumour-immune interactions in humans are limited to in vivo observational studies and in vitro culture models. The aim of this project PA 316-22 “An in vitro model for immunomodulation in melanoma” was to attempt to replicate more effectively in vitro the conditions that immune cells actually encounter in the tumour microenvironment, to examine the induction of MDSCs by cancer cells under different experimental conditions and to discover ways in which the induction of these immune suppressive cells by the tumour could circumvented. These approaches may even be more accurate than humanized mouse models, which, although representing an “in vivo incubator” and despite continuing human components, are still systemically mice. In the present project, we attempted to construct in vitro cell culture models of MDSC induction, which would allow the testing of ways to circumvent tumor induction of MDSCs, contributing to tumor escape from immunity. Established melanoma cell lines were pre-treated with inhibitors of different pathways and tested for their capacity to alleviate T cell suppression via MDSC differentiation in vitro. Targeting HSP70/90 in melanoma cells resulted in reduced induction of immune suppressive cells on a phenotypic and functional basis, for which a more potent effect was observed when HSP90 was inhibited under hypoxic conditions. This may therefore represent a realistic approach to MDSC inhibition, because drugs targeting these molecules are already in clinical use.
Publications
- (2016) A clinical and biological perspective of human myeloid-derived suppressor cells in cancer. Cellular and molecular life sciences : CMLS 73 (21) 4043–4061
Shipp, Christopher; Speigl, Lisa; Janssen, Nicole; Martens, Alexander; Pawelec, Graham
(See online at https://doi.org/10.1007/s00018-016-2278-y) - Establishing High Dimensional Immune Signatures from Peripheral Blood via Mass Cytometry in a Discovery Cohort of Stage IV Melanoma Patients. J Immunol. 2017 Jan 15;198(2):927-936
Wistuba-Hamprecht K, Martens A, Weide B, Teng KW, Zelba H, Guffart E, Chen J, Garbe C, Newell EW, Larbi A, Pawelec G
(See online at https://doi.org/10.4049/jimmunol.1600875) - Immune profiles of elderly breast cancer patients are altered by chemotherapy and relate to clinical frailty. Breast Cancer Research. 2017 19(20)
Kini Bailur, J., Pawelec, G., Hatse, S., Brouwers, B., Smeets, A., Neven, P., Laenen, A., Wildiers, H., Shipp, C.
(See online at https://doi.org/10.1186/s13058-017-0813-x) - Prognostic impact of the putative cancer stem cell markers ABCG2, CD133, ALDH1A1 and CD44V7/8 in metastatic melanoma. Br J Dermatol. 2017 177(5) pp 1447-144
Speigl, L., Janssen, N., Weide, B., Pawelec G., Shipp, C.
(See online at https://doi.org/10.1111/bjd.15194) - CD14+ HLA-DR-/low MDSCs are elevated in the periphery of early-stage breast cancer patients and suppress autologous T cell proliferation. Breast Cancer Res Treat. 2018 Apr;168(2):401-411
Speigl L., Burow, H., Bailur, J. K., Janssen, N., Walter, C.B., Pawelec, G., Shipp, C.
(See online at https://doi.org/10.1007/s10549-017-4594-9) - Immune signatures predicting responses to immunomodulatory antibody therapy. Curr Opin Immunol. 2018 Apr;51:91-96.. Epub 2018 Mar 15
Pawelec G.
(See online at https://doi.org/10.1016/j.coi.2018.03.003) - Inhibiting HSP90 prevents the induction of myeloid-derived suppressor cells by melanoma cells. Cell Immunol. 2018. May;327:68-76
Janssen, N., Speigl, L., Pawelec, G., Niessner, H., Shipp, C.
(See online at https://doi.org/10.1016/j.cellimm.2018.02.012)
