Leukocyte infiltrate in gastrointestinal adenocarcinomas is strongly associated with tumor microsatellite instability but not with tumor immunogenicity
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- Bernal, M., Concha, A., Sáenz-López, P. et al. Cancer Immunol Immunother (2011) 60: 869. doi:10.1007/s00262-011-0999-1
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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.
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).
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).
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.
KeywordsGastrointestinal adenocarcinomas (GIACs) Microsatellite instability (MSI) HLA class I Tumor leukocyte infiltrate
Antigen processing machinery
Human leukocyte antigen
Loss of heterozygosity
Major histocompatibility complex
High microsatellite instability, MSS, microsatellite stability