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

Kikuchi,Tomohiro; Mimura,Kosaku; Okayama,Hirokazu; Nakayama,Yuko; Saito,Katsuharu; Yamada,Leo; Endo,Eisei; Sakamoto,Wataru; Fujita,Shotaro; Endo,Hisahito; Saito,Motonobu; Momma,Tomoyuki; Saze,Zenichiro; Ohki,Shinji; Kono,Koji

doi:10.3892/ol.2019.10953

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

Authors:
- Tomohiro Kikuchi
- Kosaku Mimura
- Hirokazu Okayama
- Yuko Nakayama
- Katsuharu Saito
- Leo Yamada
- Eisei Endo
- Wataru Sakamoto
- Shotaro Fujita
- Hisahito Endo
- Motonobu Saito
- Tomoyuki Momma
- Zenichiro Saze
- Shinji Ohki
- Koji Kono
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Affiliations: Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960‑1295, Japan
Published online on: October 2, 2019 https://doi.org/10.3892/ol.2019.10953
Pages: 5977-5985
Copyright: © Kikuchi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].

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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.

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