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HLA class I loss in colorectal cancer: implications for immune escape and immunotherapy


T cell-mediated immune therapies have emerged as a promising treatment modality in different malignancies including colorectal cancer (CRC). However, only a fraction of patients currently respond to treatment. Understanding the lack of responses and finding biomarkers with predictive value is of great importance. There is evidence that CRC is a heterogeneous disease and several classification systems have been proposed that are based on genomic instability, immune cell infiltration, stromal content and molecular subtypes of gene expression. Human leukocyte antigen class I (HLA-I) plays a pivotal role in presenting processed antigens to T lymphocytes, including tumour antigens. These molecules are frequently lost in different types of cancers, including CRC, resulting in tumour immune escape from cytotoxic T lymphocytes during the natural history of cancer development. The aim of this review is to (i) summarize the prevalence and molecular mechanisms behind HLA-I loss in CRC, (ii) discuss HLA-I expression/loss in the context of the newly identified CRC molecular subtypes, (iii) analyze the HLA-I phenotypes of CRC metastases disseminated via blood or the lymphatic system, (iv) discuss strategies to recover/circumvent HLA-I expression/loss and finally (v) review the role of HLA class II (HLA-II) in CRC prognosis.

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Biological samples and associated data of the patients included in the study were collected, processed and provided by the Biobank for Biomedical Research and Public Health of the Valencian Community (Biobank IBSP-CV) authorized in the National Registry of Biobanks Carlos III Health Institute (code number B.0000863), which is part of the Biobank Network of Valencia and the National Biobank Network Platform (PT13/0010/0064), following standard operating procedures, and their activity is supported by Ethics Committees and Scientific Committees. This work was supported by the grants from Instituto de Salud Carlos III, co-financed by European Regional Development Fund (FEDER) [PI11/01386, PI14/01978, PI16/00752, PI17/00197 and PI18/00826]. P. A. is supported by the Consejería de Salud, Junta de Andalucía through the contract ‘Nicolás Monardes’ [C-0013-2018]. We would like to thank Dr. Mónica Bernal for her excellent help in designing and making the figures included in this review.

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Anderson, P., Aptsiauri, N., Ruiz-Cabello, F. et al. HLA class I loss in colorectal cancer: implications for immune escape and immunotherapy. Cell Mol Immunol 18, 556–565 (2021).

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  • Colorectal cancer
  • Immune escape
  • HLA Class I


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