Characterization of the immune status in the tumor microenvironment of solid cancers with chromosomal instability

Abstract

Chromosomal instability (CIN) is associated with immunosuppression in the tumor microenvironment (TME), resulting in cancer progression, metastasis, and resistance to immune checkpoint blockade therapy. We previously established a tumor immune status scoring algorithm (TIMMUSCORA) in which the immune status in the TME is evaluated numerically from activation to suppression. In the present study, we clarified the relationships between structural variation-related parameters and immunological features by applying TIMMUSCORA to solid cancers. Whole genome sequencing (WGS) and gene expression profiling (GEP) data were obtained from 394 cancer patients, and CIN-related parameters, such as the tumor mutation burden (TMB), structural variant (SV), microsatellite instability (MSI) score, ploidy, homologous recombination deficiency score, and chromothripsis (CT) and whole genome duplication (WGD) scores, were assessed. The TIMMUSCORA system demonstrated that most CIN-related parameters contributed to the low TIMMUSCORA score implicating an immunosuppressive state. Comparisons of differentially expressed genes between WGD- or CT-positive and -negative tumors showed the down-regulation of B cell markers, the down-regulation of myeloid cell markers, and the up-regulation of the NKG2D gene. In addition, the following novel observations were verified; (1) TP53 and EGFR mutation events can be associated with WGD and low TIMMUSCORA scores, and (2) NK cell activation and cancer–testis antigen gene up-regulation might be associated with CT. These results suggest that TIMMUSCORA might be useful tool evaluating immune status of CIN-harboring tumors. In future, the specific mechanism for CIN-associated immunosuppression in the tumor can be explored and clarified.