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The combination of CDX2 expression status and tumor-infiltrating lymphocyte density as a prognostic factor in adjuvant FOLFOX-treated patients with stage III colorectal cancers
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Original Article The combination of CDX2 expression status and tumor-infiltrating lymphocyte density as a prognostic factor in adjuvant FOLFOX-treated patients with stage III colorectal cancers
Ji-Ae Lee1orcid , Hye Eun Park2orcid , Hye-Yeong Jin3,4, Lingyan Jin3,4, Seung Yeon Yoo5orcid , Nam-Yun Cho4orcid , Jeong Mo Bae3,4orcid , Jung Ho Kim3orcid , Gyeong Hoon Kang3,4orcid

DOI: https://doi.org/10.4132/jptm.2024.09.26 [Epub ahead of print]
Published online: October 24, 2024
1Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
2Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea
3Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
4Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
5Pathology Center, Seegene Medical Foundation, Seoul, Korea
Corresponding author:  Gyeong Hoon Kang, Tel: +82-2-740-8263, Fax: +82-2-743-5530, 
Email: ghkang@snu.ac.kr
Received: 3 June 2024   • Revised: 22 August 2024   • Accepted: 26 September 2024
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Background
Colorectal carcinomas (CRCs) with caudal-type homeobox 2 (CDX2) loss are recognized to pursue an aggressive behavior but tend to be accompanied by a high density of tumor-infiltrating lymphocytes (TILs). However, little is known about whether there is an interplay between CDX2 loss and TIL density in the survival of patients with CRC.
Methods
Stage III CRC tissues were assessed for CDX2 loss using immunohistochemistry and analyzed for their densities of CD8 TILs in both intraepithelial (iTILs) and stromal areas using a machine learning-based analytic method.
Results
CDX2 loss was significantly associated with a higher density of CD8 TILs in both intraepithelial and stromal areas. Both CDX2 loss and a high CD8 iTIL density were found to be prognostic parameters and showed hazard ratios of 2.314 (1.050–5.100) and 0.378 (0.175–0.817), respectively, for cancer-specific survival. A subset of CRCs with retained CDX2 expression and a high density of CD8 iTILs showed the best clinical outcome (hazard ratio of 0.138 [0.023–0.826]), whereas a subset with CDX2 loss and a high density of CD8 iTILs exhibited the worst clinical outcome (15.781 [3.939–63.230]).
Conclusions
Altogether, a high density of CD8 iTILs did not make a difference in the survival of patients with CRC with CDX2 loss. The combination of CDX2 expression and intraepithelial CD8 TIL density was an independent prognostic marker in adjuvant chemotherapy-treated patients with stage III CRC.

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