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

• Verfasst von: Janikovits, Jonas [VerfasserIn]
• Verfasst von: Müller, Meike [VerfasserIn]
• Verfasst von: Körner, Sandrina [VerfasserIn]
• Verfasst von: Echterdiek, Fabian Friedrich [VerfasserIn]
• Verfasst von: Lahrmann, Bernd [VerfasserIn]
• Verfasst von: Grabe, Niels [VerfasserIn]
• Verfasst von: Schneider, Martin [VerfasserIn]
• Verfasst von: Knebel Doeberitz, Magnus von [VerfasserIn]
• Verfasst von: Kloor, Matthias [VerfasserIn]
• Titel: High numbers of PDCD1 (PD-1)-positive T cells and B2M mutations in microsatellite-unstable colorectal cancer
• Verf.angabe: Jonas Janikovits, Meike Müller, Julia Krzykalla, Sandrina Körner, Fabian Echterdiek, Bernd Lahrmann, Niels Grabe, Martin Schneider, Axel Benner, Magnus von Knebel Doeberitz, Matthias Kloor
• Jahr des Originals: 2017
• Fussnoten: Published online: 06 Nov 2017 ; Gesehen am 12.07.2018
• Titel Quelle: Enthalten in: OncoImmunology
• Jahr Quelle: 2018
• Band/Heft Quelle: 7(2018,2) Artikel-Nummer 1390640, 9 Seiten
• ISSN Quelle: 2162-402X
• DOI: doi:10.1080/2162402X.2017.1390640
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1577539680

Abstract

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.