J Pathol Transl Med.  2025 Jan;59(1):50-59. 10.4132/jptm.2024.09.26.

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

• Lee JA
• Park HE
• Jin HY
• Jin L
• Yoo SY
• Cho NY
• Bae JM
• Kim JH
• Kang GH

• KMID: 2563884
• DOI: http://doi.org/10.4132/jptm.2024.09.26

Abstract

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.

Keyword

CD8 antigens; CDX2 transcription factor; Colorectal neoplasms; Prognosis; Lymphocytes, tumor-infiltrating

Figure

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  Fig. 1. Representative cases of colorectal carcinomas (CRCs) with retained caudal-type homeobox 2 (CDX2) expression and a low CD8 intraepithelial tumor-infiltrating lymphocyte (iTIL) density (A, C) and with CDX2 loss and a high CD8 iTIL density (B, D).

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  Fig. 2. Comparison of intraepithelial or stromal tumor-infiltrating lymphocyte (iTIL or sTIL) density between colorectal carcinomas with and without CDX2 loss. CDX2–, expressional loss of CDX2; CDX2+, retained expression of CDX2.

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  Fig. 3. Kaplan-Meier curves of cancer-specific survival (A, C) and recurrence-free survival (B, D) in adjuvant FOLFOX-treated patients with stage III colorectal carcinoma (CRC) according to caudal-type homeobox 2 (CDX2) expression status (A, B) and CD8 intraepithelial tumor-infiltrating lymphocyte (iTIL) density status (C, D). CDX2+ (retained expression, n = 442) and CDX2- (loss of expression, n = 63); CD8 iTIL-high (n = 223) and CD8 iTIL-low CRC (n = 223).

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  Fig. 4. Kaplan-Meier survival curves of cancer-specific survival (A) and recurrence-free survival (B). Kaplan-Meier survival analysis with the log-rank test was performed in adjuvant FOLFOX-treated patients with stage III colorectal carcinoma according to the combination of caudal-type homeobox 2 (CDX2) expression and CD8 intraepithelial tumor-infiltrating lymphocyte (iTIL) density. CDX2+ (CDX2 retained)/CD8 iTIL-high (n = 188); CDX2+/CD8 iTIL-low (n = 209); CDX2– (CDX2 loss)/CD8 iTIL-high (n = 30); CDX2–/CD8 iTIL-low (n = 19).

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