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High numbers of PDCD1 (PD-1)-positive T cells and B2M mutations in microsatellite-unstable colorectal cancer

DNA mismatch repair (MMR)-deficient cancers accumulate high numbers of coding microsatellite mutations, which lead to the generation of highly immunogenic frameshift peptide (FSP) neoantigens. MMR-deficient cells can grow out to clinically manifest cancers either if they evade immune cell attack or...

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Hauptverfasser: Janikovits, Jonas (VerfasserIn) , Müller, Meike (VerfasserIn) , Körner, Sandrina (VerfasserIn) , Echterdiek, Fabian Friedrich (VerfasserIn) , Lahrmann, Bernd (VerfasserIn) , Grabe, Niels (VerfasserIn) , Schneider, Martin (VerfasserIn) , Knebel Doeberitz, Magnus von (VerfasserIn) , Kloor, Matthias (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2018
In: OncoImmunology
Year: 2017, Jahrgang: 7, Heft: 2, Pages: e1390640-1-e1390640-9
ISSN:2162-402X
DOI:10.1080/2162402X.2017.1390640
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1080/2162402X.2017.1390640
Verlag, Volltext: http://dx.doi.org/10.1080/2162402X.2017.1390640
Volltext
Verfasserangaben:Jonas Janikovits, Meike Müller, Julia Krzykalla, Sandrina Körner, Fabian Echterdiek, Bernd Lahrmann, Niels Grabe, Martin Schneider, Axel Benner, Magnus von Knebel Doeberitz, Matthias Kloor
Beschreibung
Zusammenfassung:DNA mismatch repair (MMR)-deficient cancers accumulate high numbers of coding microsatellite mutations, which lead to the generation of highly immunogenic frameshift peptide (FSP) neoantigens. MMR-deficient cells can grow out to clinically manifest cancers either if they evade immune cell attack or if local T-cells get exhausted. Therefore, a subset of MSI cancer patients responds particularly well to treatment with immune checkpoint inhibitors. We analyzed whether immune evasion in MMR-deficient cancer mediated by loss of HLA class I or II antigens is related to local immune cell activation status. Microsatellites located in Beta2-microglobulin (B2M) and the HLA class II-regulatory genes RFX5 and CIITA were analyzed for mutations in MMR-deficient colorectal cancers (n = 53). The results were related to CD3-positive and PDCD1 (PD-1)-positive T-cell infiltration. PDCD1 (PD-1)-positive T-cell counts were significantly higher in B2M-mutant compared to B2M-wild type tumors (median: 22.2 cells per 0.25 mm2 vs. 2.0 cells per 0.25 mm2, Wilcoxon test p = 0.002). Increasing PDCD1 (PD-1)-positive T-cell infiltration was significantly related to an increased likelihood of B2M mutations (OR = 1.81). HLA class II antigen expression status was significantly associated with enhanced overall T-cell infiltration, but not related to PDCD1 (PD-1)-positive T-cells. These results suggest that immune evasion mediated by B2M mutation-induced loss of HLA class I antigen expression predominantly occurs in an environment of activated PDCD1 (PD-1)-positive T cell infiltration. If B2M mutations interfere with anti-PDCD1 (PD-1)/CD274 (PD-L1) therapy success, we predict that resistance towards anti-PDCD1 (PD-1) therapy may - counterintuitively - be particularly common in patients with MMR-deficient cancers that show high PDCD1 (PD-1)-positive T cell infiltration.
Beschreibung:Online veröffentlicht: 06 Nov 2017
Gesehen am 29.10.2024
Beschreibung:Online Resource
ISSN:2162-402X
DOI:10.1080/2162402X.2017.1390640

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