Complex pattern of immune evasion in MSI colorectal cancer
- 13 March 2018
- journal article
- research article
- Published by Taylor & Francis Ltd in OncoImmunology
- Vol. 7 (7), e1445453
- https://doi.org/10.1080/2162402x.2018.1445453
Abstract
Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation, and 54% of these mutations were predicted to abrogate function. Mutations affecting the HLA class I transactivator NLRC5 were observed as a potential new immune evasion mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in MMR-deficient cancers were associated with decreased levels of HLA class I antigen expression. In summary, the majority of MMR-deficient cancers display mutations interfering with HLA class I antigen presentation that reflect active immune surveillance and immunoselection during tumor development. Clinical studies focusing on immune checkpoint blockade in MSI cancer should account for the broad variety of immune evasion mechanisms as potential biomarkers of therapy success.Keywords
Funding Information
- Wilhelm Sander Foundation (2016.056.1)
- Deutsche Forschungsgemeinschaft (KFO 227)
This publication has 40 references indexed in Scilit:
- Mismatch Repair Deficiency and Response to Immune Checkpoint BlockadeThe Oncologist, 2016
- JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrationsScientific Reports, 2013
- Prognostic impact of β-2-microglobulin expression in colorectal cancers stratified by mismatch repair statusJournal of Clinical Pathology, 2012
- The immune response to sporadic colorectal cancer in a novel mouse modelOncogene, 2010
- NLR family member NLRC5 is a transcriptional regulator of MHC class I genesProceedings of the National Academy of Sciences of the United States of America, 2010
- The Predictive Value of HLA Class I Tumor Cell Expression and Presence of Intratumoral Tregs for Chemotherapy in Patients with Early Breast CancerClinical Cancer Research, 2010
- Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal CancersCancer Research, 2005
- Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastasesBritish Journal of Cancer, 2005
- High Prevalence of Activated Intraepithelial Cytotoxic T Lymphocytes and Increased Neoplastic Cell Apoptosis in Colorectal Carcinomas with Microsatellite InstabilityThe American Journal of Pathology, 1999
- Mutations of the β2‐microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptidesTissue Antigens, 1998