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J Cancer. 2018 Oct 21;9(23):4325-4333. doi: 10.7150/jca.27735. eCollection 2018.

The Clinical and Biomarker Association of Programmed Death Ligand 1 and its Spatial Heterogeneous Expression in Colorectal Cancer.

Author information

1
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
2
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
3
Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
4
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.

Abstract

Background: Programmed death ligand 1 (PD-L1) expression has been shown to predict benefit from anti-PD-1 treatment in several cancers. However, its predictive value in colorectal cancer seems limited. This study was aimed to explore the clinical and biomarker association of programmed death ligand 1 and its spatial heterogeneous expression in colorectal cancer. Methods: Tissue microarrays of 422 primary colorectal cancers from our hospital were used for the interpretation of PD-L1 and programmed death 1 (PD-1) expression, cluster of differentiation 4 (CD4) and CD8 density and microsatellite instability (MSI) status by immunohistochemistry. To assess the spatial heterogeneity of PD-L1 expression, Tissue microarrays of 383 paired intra-primary-tumor tissues, and 105 paired lymph node metastatic tumors and 64 paired distant metastatic tumors were also used. Results: PD-L1 was positive in 188 (44.5%) primary colorectal cancers. PD-L1 expression was associated with less advanced N category (P<0.001), less advanced TNM stage (P<0.001) and less nervous invasion (P=0.04). Higher PD-L1 expression was associated with higher PD-1 expression (P<0.001), higher CD4 (P<0.001) and CD8 (P<0.001) density and DNA mismatch repair deficiency (P=0.01). PD-L1 expression was associated with better disease-free survival and overall survival, but it was only an independent prognostic factor for disease-free survival (hazard ratio and 95% confidence interval: 0.42 [0.25-0.72], P<0.001). The probability of inconsistent PD-L1 expression was respectively 17.8%, 31.4% and 39.1% within primary tumors, between primary tumors and lymph node metastatic tumors, and between primary tumors and distant metastatic tumors. All the three differences were statistically significant (P<0.001, P<0.001 and P=0.05, respectively). Conclusions: PD-L1 expression was a marker of pre-existing immune responses in colorectal cancer, however, it was heterogeneously expressed in colorectal cancer, especially between primary and metastatic tumors. This might partially explain the low-efficiency of its predictive value for benefit from anti-PD-1 treatment.

KEYWORDS:

colorectal cancer; heterogeneity; microsatellite instability; programmed death ligand 1; tumor-infiltrating immune cells

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

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