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MHC CLASS I LOSS AND CANCER IMMUNE ESCAPE

MHC CLASS I LOSS AND CANCER IMMUNE ESCAPE

Speaker: Federico Garrido

Universidad de Granada [Granada, Spain]
Host: Pedro A. Lazo-Zbikowski

Fecha: 25/04/2019

Hora: 12:30

Salón de actos del Centro de Investigación del Cáncer

Most tumor cells derive from MHC-I-positive normal counterparts and remain positive at early stages of tumor development. T lymphocytes can infiltrate tumor tissue, recognize and destroy MHC class I (MHC-I) positive cancer cells (“permissive” phase I). This phase end in the total destruction of the tumor with no clinical evidence. Alternatively, MHC-I-negative tumor cell variants resistant to T-cell killing can emerge. During this process of T cell immune selection, tumors first acquire a heterogeneous MHC-I expression pattern and finally become uniformly MHC-I negative. At this stage (phase II) tumour cells actively create an immunosupresive microenviroment that prevents intra-tumour T/NK cell infiltration and produces a “non-permissive” encapsulated structure with tumor nodes surrounded by fibrous tissue containing different elements including leukocytes, macrophages, fibroblasts, Tregs, MDSCs etc. The transition from phase I to phase II probably last for a short period of time.This phase II is associated with a peculiar tumour tissue architecture well defined by pathologists long time ago but not previously associated with the absence of HLA-I molecules. This tissue structure resembles that observed in different TH2 granulomas in which the pathogen cannot be destroyed but is isolated from the body by a biological barrier. Molecular mechanisms responsible for total or partial MHC-I downregulation play a crucial role in determining and predicting the antigen-presenting capacity of cancer cells. MHC-I downregulation caused by reversible (“soft”) lesions can be upregulated by TH1-type cytokines released into the tumor microenvironment in response to different types of immunotherapy. In contrast, when the molecular mechanism of the tumor MHC-I loss is irreversible (“hard”) due to a genetic defect in the gene/s coding for MHC-I heavy chains (chromosome 6), beta-2-microglobulin (β2M) (chromosome 15) or IFN genes, malignant cells are unable to upregulate MHC-I, remain undetectable by cytotoxic T-cells and continue to grow and metastasize. Based on the tumor MHC-I molecular analysis, it might be possible to define MHC-I phenotypes present in cancer patients in order to distinguish between responders versus non-responders. This highlight the need for designing strategies to enhance tumor MHC-I expression that would allow CTL-mediated tumor rejection. These results will be discussed in the context of the new era of Cancer Immunotherapy and the use of monoclonal antibodies that regulate T cell cytotoxicity.