Beschreibung:
Abstract Background and Aims: DNA mismatch repair-deficient cancers show microsatellite instability (MSI) and accumulate high numbers of somatic insertion/deletion mutations at repetitive sequence stretches. The high mutational load of MSI cancers leads to the generation of multiple frameshift peptide (FSP) neoantigens, which are highly immunogenic and recognized by the immune system as foreign antigens. MSI cancers respond particularly well to treatment with immune checkpoint inhibitors such as anti-PD-1 antibodies. We systematically analyzed immune evasion phenomena in MSI cancers and aimed to identify factors that are related to and potentially determine PD-1 expression on tumor-infiltrating lymphocytes, focusing on alterations of HLA class I and II antigen presentation pathways in cancer cells. Methods: Microsatellites located in Beta2-microglobulin (B2M) and the HLA class II-regulatory genes RFX5 and CIITA were analyzed for mutations in MSI colorectal cancer specimens (n = 53). HLA class I and II antigen expression was examined by immunohistochemistry. In addition, tumor-infiltrating lymphocytes (CD3-positive T cells, PD-1-positive T cells) were quantified using a semi-automated system. Results: We related B2M mutation and HLA class II antigen expression status of MSI colorectal cancer specimens (n = 56) to CD3- and PD-1 positive T cell infiltration in the tumor. PD-1-positive T cell infiltration was significantly higher in B2M-mutant (mt) compared to B2M-wild type (wt) tumors (median: 22.2 cells per 0.25 mm2 in B2M-mt vs. 2.0 cells per 0.25 mm2 in B2M-wt, Wilcoxon's rank sum test p = 0.002). Increasing PD-1-positive T cell infiltration was significantly related to an increased likelihood of B2M mutation and loss of HLA class I antigen expression (OR = 1.81). In contrast, HLA class II antigen expression status was not related to the proportion of PD-1-positive lymphocytes, but significantly associated with enhanced overall T cell infiltration. Conclusions: 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 PD-1-positive T cell infiltration, supporting the validity of the immunoediting concept in MSI colorectal cancers. Moreover, B2M mutation status may predict therapy resistance against anti-PD-1 therapy. Note: This abstract was not presented at the conference. Citation Format: Matthias Kloor, Jonas Janikovits, Julia Krzykalla, Axel Benner, Niels Grabe, Fabian Echterdiek, Meike Mueller, Sandrina Koerner, Aysel Ahadova, Magnus von Knebel Doeberitz. Immune evasion and PD-1-positive T cell infiltration in DNA mismatch repair-deficient colorectal cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A085.