A subset of patients with MSS/MSI‑low‑colorectal cancer showed increased CD8(+) TILs together with up‑regulated IFN‑γ

Abstract

A small subset of patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS)-colorectal cancer (CRC) benefit from immunotherapy with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade. Therefore, the aim of the current study was to evaluate the immune status of patients with pMMR/microsatellite instability-low (MSI-L)/MSS-CRC and deficient MMR (dMMR)/MSI-high (MSI-H)-CRC in order to identify responders to anti-PD-1/PD-L1 inhibitors. The current study used a dataset downloaded from The Cancer Genome Atlas (TCGA) as well as 219 clinical tissue samples to investigate the infiltrating grade of cluster of differentiation (CD) 4 and CD8 tumor infiltrating lymphocytes (TILs), the expression levels of PD-L1 and PD-L2, the interferon-γ (IFN-γ) and CD8 T effector gene signatures, and the phosphorylated signal transducer and activator of transcription 1 (p-STAT1) status in patients with pMMR/MSI-L/MSS-CRC and dMMR/MSI-H-CRC. Analysis of TCGA dataset revealed that the mRNA expression levels of PD-L1 and PD-L2, the IFN-γ gene signature and the CD8 T effector gene signature were significantly upregulated in MSI-H tumors compared with MSI-L/MSS tumors. Additionally, a subpopulation of patients with upregulation of the IFN-γ and CD8 T effector gene signatures was observed in those with MSI-L/MSS-CRC. Immunohistochemical staining of the clinical samples revealed a subpopulation of patients with pMMR-CRC that were positive for PD-L1 and p-STAT1, and whom had levels of elevated CD8(+) and CD4(+) TILs infiltration similar to those observed in patients with dMMR-CRC. The results obtained in the current study suggested that a subpopulation of patients with MSI-L/MSS-CRC and pMMR-CRC with upregulated IFN-γ and CD8 T effector gene signatures may benefit from immunotherapy with antibodies against PD-1 and PD-L1.

Association between apoptosis inhibitor of macrophage and microsatellite instability status in colorectal cancer

“…Consistent to our results, previous studies showed that the CD8 T effector gene signature was significantly upregulated in MSI-H tumors compared with MSI-L/MSS tumors [ 28 ]. Moreover, a report demonstrated that CD8(+) cytotoxic T lymphocytes may lead to increased platelet destruction in immune thrombocytopenia [ 29 ].…”

Development and interpretation of a pathomics-based model for the prediction of microsatellite instability in Colorectal Cancer

“…Despite advances in understanding of MSI at the genomic level, the process and mechanisms at the transcriptomic level remain relatively understudied. Researches on the anti-tumor effects of MSI have suggested an increased activation and infiltration of immune cells, together with an enhanced cytolytic activity as well as an up-regulation of CD8 + T-effector genes 29 , 43 . Remarkably, by analyzing the WGCNA-identified modules, the pathological signatures were demonstrated with high relevance to the expression level of IFN-γ-JAK-STAT1 signaling pathway, whose pivotal role in immune activation and response to immunotherapy has been supported by extensive evidence 44 .…”

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

“…The vast majority of CRC cases, MSS or pMMR CRC, are naturally resistant to immunotherapy; at least in part due to the low antigenicity (TMB) of the malignancy. However, based on TCGA dataset analysis, a small subset of patients among MSI-Low/MSS-CRC cases exhibiting a high CD8 + T cell infiltrate and an upregulation of IFN-γ could benefit from immunotherapies ( 98 ).…”