Abstract
A new paradigm for understanding immune-surveillance and immune escape in cancer is described here. Metastatic carcinomas express reduced levels of IL-33 and diminished levels of antigen processing machinery (APM), compared to syngeneic primary tumours. Complementation of IL-33 expression in metastatic tumours upregulates APM expression and functionality of major histocompatibility complex (MHC)-molecules, resulting in reduced tumour growth rates and a lower frequency of circulating tumour cells. Parallel studies in humans demonstrate that low tumour expression of IL-33 is an immune biomarker associated with recurrent prostate and kidney renal clear cell carcinomas. Thus, IL-33 has a significant role in cancer immune-surveillance against primary tumours, which is lost during the metastatic transition that actuates immune escape in cancer.
Highlights
The gene expression profile in tumour tissue is influenced, to a significant extent, by the local microenvironment through the connective tissue framework
We find that down-modulation of IL-33 and major histocompatibility complex (MHC)-I/Human leukocyte antigen (HLA) related genes are associated with progression to metastatic disease and discover that IL-33 downregulation is a biomarker associated with recurrence in human metastatic prostate and kidney renal clear cell carcinomas
We have found that IL-33 gene expression by tumours complements MHC-I production and immune recognition of processed tumour antigens, and, reduces the frequency of circulating tumour cells and the growth of metastatic tumours in vivo
Summary
The gene expression profile in tumour tissue is influenced, to a significant extent, by the local microenvironment through the connective tissue framework. This framework consists of normal cells, including. It is generally accepted that tumour-infiltrating immune cells are intimately linked to the kinetics of tumour growth, via direct contact and via chemokine-, cytokine-related signalling pathways. We have found that IL-33 gene expression by tumours complements MHC-I production and immune recognition of processed tumour antigens, and, reduces the frequency of circulating tumour cells and the growth of metastatic tumours in vivo. This study demonstrates that immunosubversion of the IL-33-dependent antigen processing pathways in metastatic forms of the cancer is a new paradigm for understanding both immune-surveillance and immune escape in malignancy
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