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

Research Paper

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

Xiao-Li Wei1*, Qi-Nian Wu2*, Dong-liang Chen1*, Zhao-Lei Zeng2, Jia-Bin Lu3, Ze-Xian Liu2, Huai-Qiang Ju2, Chao Ren1, Zhi-Zhong Pan4, Feng-Hua Wang1✉, Rui-Hua Xu1✉

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.
*Xiao-Li Wei, Qi-Nian Wu and Dong-liang Chen contributed equally to this study.

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, programmed death ligand 1, microsatellite instability, tumor-infiltrating immune cells, heterogeneity

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How to cite this article:
Wei XL, Wu QN, Chen Dl, Zeng ZL, Lu JB, Liu ZX, Ju HQ, Ren C, Pan ZZ, Wang FH, Xu RH. The Clinical and Biomarker Association of Programmed Death Ligand 1 and its Spatial Heterogeneous Expression in Colorectal Cancer. J Cancer 2018; 9(23):4325-4333. doi:10.7150/jca.27735. Available from http://www.jcancer.org/v09p4325.htm