Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer

Abstract

In this study, we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer (CRC). To this end, 186 microsatellite instability-high (MSI-H) and 153 microsatellite stable (MSS) CRCs were subjected to immunohistochemistry (IHC) analysis for the expression of CD274 and mismatch repair proteins. CD274 expression was evaluated in tumor cells at the center (TC) and periphery (TP), and immune cells at the center (IC) and periphery (IP) of CRC. IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density. Additionally, samples were screened for the B-Raf (BRAF)-V600E mutation using a Cobas 4800 System and IHC. In total, CD274, CD274, CD274, and CD274 were observed in 43 (23.1%), 47 (25.3%), 107 (57.5%), and 102 (54.8%) of the MSI-H CRCs examined, and in three (2.0%), four (2.6%), 47 (30.7%), and 56 (36.6%) of the 153 MSS CRCs tested. Meanwhile, intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 (12.9%) and 47 (25.3%) MSI-H CRCs, respectively. Notably, in both MSI-H and MSS CRC, CD274 and CD274 were independently associated with improved prognosis (P < 0.05), while BRAF mutation was associated with CD274, poor differentiation, sporadic type, and hMLH1(-)/hMSH2(+)/hMSH6(+)/PMS2(-) in MSI-H CRC (P < 0.006). In conclusion, CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients. A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies.

The expression of programed death ligand‐1 could be related with unfavorable prognosis in salivary duct carcinoma

“…The association between the expressions of PD‐L1, PD‐L2 and PD‐1 in TIMC and prognosis is controversial. Several possibilities have been considered . In salivary gland carcinomas, Mukaigawa et al and Harada et al examined PD‐L1 expression in TIMC and demonstrated that cases with positive PD‐L1 expression had a significantly unfavorable prognosis by Kaplan‐Meier method .…”

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

“…Whereas immune cell-specific PD-L1 expression was found to be an independent prognostic factor, tumour cell-specific PD-L1 expression was not associated with survival neither in the full cohort nor in subgroup analysis according to PTL, supporting previous reports in CRC 16 , 17 , 19 , 22 and other cancers. 32-34 Nonetheless, an abundance of studies have reported high PD-L1 expression to be associated with an impaired prognosis due to induction of immune evasion, 6 , 7 , 35 being the rationale for PD-1/PD-L1 blockade.…”

“…17 , 19 , 22 Moreover, in subsite analysis according to PTL, PD-L1 expression was independently associated with a prolonged survival in patients with right-sided and left-sided colon cancers, but not in patients with rectal cancer. These findings further support previous evidence suggesting that proximal and distal CRC may represent different epidemiological, pathological, genetic, and clinical entities.…”

Programmed cell death ligand‐1 protein expression and CD274/PD‐L1 gene amplification in colorectal cancer: Implications for prognosis

“…These findings might be attributed to a bystander effect of TIL infiltration; in fact, the number of PD‐L1‐positive TILs was associated with TIL density, implying that PD‐L1‐positive immune cells increased proportionally to the intratumoral immune reaction . However, Darb‐Esfahani et al reported that positive prognoses associated with PD‐L1‐positive TILs are independent of the number of T cells; in our previous study, there was no evidence that PD‐L1 expression was related to the density of TILs . The complex interaction between immune effector cells and the tumor microenvironment very likely impacts the biological significance of particular immune markers and also appears to be dependent on the tumor type.…”

“…Previous studies revealed an association between unfavorable clinical outcomes and tumoral PD-L1 expression in patients with CRC, 11,17,18 whereas other studies found no such associations. 9,19 Some researchers suggested that the prognostic implication of PD-L1 expression might depend on the mismatch repair status, 8,10 but the outcomes were inconsistent. Our own survival analysis showed that the expression of PD-L1 was correlated with poorer clinical outcomes in patients with CRC.…”