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Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer

Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitor...

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Autores principales: Sugimura-Nagata, Akane, Koshino, Akira, Inoue, Satoshi, Matsuo-Nagano, Aya, Komura, Masayuki, Riku, Miho, Ito, Hideaki, Inoko, Akihito, Murakami, Hideki, Ebi, Masahide, Ogasawara, Naotaka, Tsuzuki, Toyonori, Takahashi, Satoru, Kasugai, Kunio, Kasai, Kenji, Inaguma, Shingo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975978/
https://www.ncbi.nlm.nih.gov/pubmed/33799989
http://dx.doi.org/10.3390/ijms22052690
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author Sugimura-Nagata, Akane
Koshino, Akira
Inoue, Satoshi
Matsuo-Nagano, Aya
Komura, Masayuki
Riku, Miho
Ito, Hideaki
Inoko, Akihito
Murakami, Hideki
Ebi, Masahide
Ogasawara, Naotaka
Tsuzuki, Toyonori
Takahashi, Satoru
Kasugai, Kunio
Kasai, Kenji
Inaguma, Shingo
author_facet Sugimura-Nagata, Akane
Koshino, Akira
Inoue, Satoshi
Matsuo-Nagano, Aya
Komura, Masayuki
Riku, Miho
Ito, Hideaki
Inoko, Akihito
Murakami, Hideki
Ebi, Masahide
Ogasawara, Naotaka
Tsuzuki, Toyonori
Takahashi, Satoru
Kasugai, Kunio
Kasai, Kenji
Inaguma, Shingo
author_sort Sugimura-Nagata, Akane
collection PubMed
description Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observations, drugs targeting the macrophage checkpoint have been developed with the expectation of anti-cancer effects against T-cell immune checkpoint inhibitor-refractory tumors. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD47, SIRPA, CD68, and CD163 expression to assess their predictive utility and the applicability of CD47–SIRPA axis-modulating drugs. Thirty-five percent of the lesions (95/269) displayed CD47 expression on the cytomembrane of CRC cells. CRCs contained various numbers of tumor-associated immune cells (TAIs) with SIRPA, CD68, or CD163 expression. The log-rank test revealed that patients with CD47-positive CRCs had significantly worse survival than CD47-negative patients. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio (R) = 0.23), age < 70 years (HR = 0.48), and high SIRPA-positive TAI counts (HR = 0.55) as potential favorable factors. High tumor CD47 expression (HR = 1.75), lymph node metastasis (HR = 2.26), and peritoneal metastasis (HR = 5.80) were cited as potential independent risk factors. Based on our observations, CD47–SIRPA pathway-modulating therapies may be effective in patients with CRC.
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spelling pubmed-79759782021-03-20 Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer Sugimura-Nagata, Akane Koshino, Akira Inoue, Satoshi Matsuo-Nagano, Aya Komura, Masayuki Riku, Miho Ito, Hideaki Inoko, Akihito Murakami, Hideki Ebi, Masahide Ogasawara, Naotaka Tsuzuki, Toyonori Takahashi, Satoru Kasugai, Kunio Kasai, Kenji Inaguma, Shingo Int J Mol Sci Article Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observations, drugs targeting the macrophage checkpoint have been developed with the expectation of anti-cancer effects against T-cell immune checkpoint inhibitor-refractory tumors. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD47, SIRPA, CD68, and CD163 expression to assess their predictive utility and the applicability of CD47–SIRPA axis-modulating drugs. Thirty-five percent of the lesions (95/269) displayed CD47 expression on the cytomembrane of CRC cells. CRCs contained various numbers of tumor-associated immune cells (TAIs) with SIRPA, CD68, or CD163 expression. The log-rank test revealed that patients with CD47-positive CRCs had significantly worse survival than CD47-negative patients. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio (R) = 0.23), age < 70 years (HR = 0.48), and high SIRPA-positive TAI counts (HR = 0.55) as potential favorable factors. High tumor CD47 expression (HR = 1.75), lymph node metastasis (HR = 2.26), and peritoneal metastasis (HR = 5.80) were cited as potential independent risk factors. Based on our observations, CD47–SIRPA pathway-modulating therapies may be effective in patients with CRC. MDPI 2021-03-07 /pmc/articles/PMC7975978/ /pubmed/33799989 http://dx.doi.org/10.3390/ijms22052690 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Sugimura-Nagata, Akane
Koshino, Akira
Inoue, Satoshi
Matsuo-Nagano, Aya
Komura, Masayuki
Riku, Miho
Ito, Hideaki
Inoko, Akihito
Murakami, Hideki
Ebi, Masahide
Ogasawara, Naotaka
Tsuzuki, Toyonori
Takahashi, Satoru
Kasugai, Kunio
Kasai, Kenji
Inaguma, Shingo
Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer
title Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer
title_full Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer
title_fullStr Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer
title_full_unstemmed Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer
title_short Expression and Prognostic Significance of CD47–SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer
title_sort expression and prognostic significance of cd47–sirpa macrophage checkpoint molecules in colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975978/
https://www.ncbi.nlm.nih.gov/pubmed/33799989
http://dx.doi.org/10.3390/ijms22052690
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