Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability

Shotaro Korehisa, Eiji Oki, Makoto Iimori, Yu Nakaji, Mototsugu Shimokawa, Hiroshi Saeki, Shinji Okano, Yoshinao Oda, Yoshihiko Maehara

Research output: Contribution to journalArticle

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Abstract

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front.

Original languageEnglish
Pages (from-to)822-832
Number of pages11
JournalInternational Journal of Cancer
Volume142
Issue number4
DOIs
Publication statusPublished - Feb 15 2018

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Microsatellite Instability
Colorectal Neoplasms
Cell Death
Ligands
CD274 Antigen
Microsatellite Repeats
Neoplasms
Macrophages
Tumor Escape
N-methylsuccinimide
Propensity Score
Tumor Microenvironment
Myeloid Cells
Immunotherapy
Blood Vessels
Adenocarcinoma

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability. / Korehisa, Shotaro; Oki, Eiji; Iimori, Makoto; Nakaji, Yu; Shimokawa, Mototsugu; Saeki, Hiroshi; Okano, Shinji; Oda, Yoshinao; Maehara, Yoshihiko.

In: International Journal of Cancer, Vol. 142, No. 4, 15.02.2018, p. 822-832.

Research output: Contribution to journalArticle

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abstract = "Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4{\%} and 36.1{\%} of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27{\%} and 72.2{\%} of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front.",
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AU - Korehisa, Shotaro

AU - Oki, Eiji

AU - Iimori, Makoto

AU - Nakaji, Yu

AU - Shimokawa, Mototsugu

AU - Saeki, Hiroshi

AU - Okano, Shinji

AU - Oda, Yoshinao

AU - Maehara, Yoshihiko

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