Abstract
Purpose
To analyze the correlation of genomic instability with leukocyte infiltrate in gastrointestinal carcinomas (GIACs) and with tumor immunogenicity, e.g., HLA class I cell surface expression defects and galectin-3 and PDL-1 expression.
Experimental design
Lymphocyte and macrophage infiltrations were immunohistochemically studied in HLA class I negative GIACs with sporadic high-level microsatellite instability (MSI-H) or microsatellite stability (MSS).
Results
Tumors with MSI-H were associated with the following: dense infiltration (CD45, P < 0.001); cytotoxic CD8-positive lymphocytes (P < 0.001); and a complete absence of HLA class I cell surface expression, due to inactivating β2-microglobulin (β2-m) mutation in 50% of cases. In contrast, HLA class I negative tumors with MSS were significantly associated with fewer CD8-positive lymphocytes. There was no association between microsatellite instability and other molecular features of the tumor cells, including expression of galectin-3. Finally, macrophage infiltrate in the tumors was not correlated with microsatellite instability or HLA class I cell surface expression (CD64, P = 0.63; CD163, P = 0.51).
Conclusions
Microsatellite instability appears to be the most important factor determining the composition, density, and localization of leukocyte infiltrate, which is independent of other molecular features such expression of HLA class I cells, galectin-3, or programmed death ligand-1. Accordingly, the strong intratumoral CD8+ T infiltration of MSI-H tumors may be produced by elevated levels of specific inflammatory chemokines in the tumor microenvironment.
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Abbreviations
- APM:
-
Antigen processing machinery
- CRC:
-
Colorectal cancer
- GIAC:
-
Gastrointestinal adenocarcinoma
- HLA:
-
Human leukocyte antigen
- LOH:
-
Loss of heterozygosity
- MHC:
-
Major histocompatibility complex
- MMR:
-
Mismatch repair
- MSI:
-
Microsatellite instability
- MSI-H:
-
High microsatellite instability, MSS, microsatellite stability
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Acknowledgments
The authors thank Eva García, Antonia Moreno, Mª Dolores Gálvez and Inmaculada García for technical assistance. They also thank the Tumor-Tissue Biobank of Virgen de las Nieves University Hospital for providing samples. The study was partially supported by grants from the Fondo de Investigaciones Sanitarias (08/0528), Red Genómica del Cáncer (RETICRD 06/020), Consejería de Salud Junta de Andalucía, Proyecto de Investigación de Excelencia (CTS-3952, CVI-4740 and P06/-CTS-02200) and Plan Andaluz de Investigación (PAI, Group CTS- in Spain, and from the European Searchable Tumour Cell Line Database (ESTDAB) project, contract No. QLRI-CT-2001-01325 (http://www.ebi.ac.uk/estdab), from the European Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumor immunology (ENACT) project (European community LSHC-CT-2004-503306) and from the Cancer Immunotherapy Project (European community OJ 2004/c158,18234).
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The authors declare that they have no conflict of interests.
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Bernal, M., Concha, A., Sáenz-López, P. et al. Leukocyte infiltrate in gastrointestinal adenocarcinomas is strongly associated with tumor microsatellite instability but not with tumor immunogenicity. Cancer Immunol Immunother 60, 869–882 (2011). https://doi.org/10.1007/s00262-011-0999-1
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DOI: https://doi.org/10.1007/s00262-011-0999-1