Intratumoral Cytotoxic T-Lymphocyte Density and PD-L1 Expression Are Prognostic Biomarkers for Patients with Colorectal Cancer

Abstract

Background and objectives: Cytotoxic T-lymphocyte (CTL)-mediated inflammatory response to tumors plays a crucial role in preventing the progression of some cancers. Programmed cell death ligand 1 (PD-L1), a cell-surface glycoprotein, has been reported to repress T-cell-mediated immune responses against tumors. However, the clinical significance of PD-L1 in colorectal cancer (CRC) remains unclear. Our aim was to elucidate the prognostic significance of PD-L1 expression and CD8+ CTL density in CRC. Materials and methods: CD8 and PD-L1 immunostaining was conducted on 157 pathologic specimens from patients with CRC. The CD8+ CTL density and PD-L1 expression within the tumor microenvironment were assessed by immunohistochemistry. Results: Tumor invasion (pT) was significantly correlated with intratumoral (p = 0.011) and peritumoral (p = 0.016) CD8+ CTLs density in the tumor microenvironment. In addition, there was a significant difference in the intensity of CD8+ CTLs between patients with and without distant metastases (intratumoral p = 0.007; peritumoral p = 0.037, T-test). Lymph node metastasis (pN) and TNM stage were significantly correlated with PD-L1 expression in CRC cells (p = 0.015, p = 0.029, respectively). Multivariate analysis revealed a statistically significant relationship between the intratumoral CD8+ CTL density and disease-free survival (DFS) (hazard ratio [HR] 2.06; 95% confidence interval [CI]: 1.01–4.23; p = 0.043). The DFS was considerably shorter in patients with a high expression of PD-L1 in cancer cells than those with a low expression (univariate HR 2.55; 95% CI 1.50–4.34; p = 0.001; multivariate HR 0.48; 95% CI 0.28–0.82; p = 0.007). Conversely, patients with high PD-L1 expression in tumor-infiltrating lymphocytes had a longer DFS in both univariate analysis (HR 0.25; 95% CI: 0.14–0.44; p < 0.001) and multivariate analysis (HR 3.42; 95% CI: 1.95–6.01; p < 0.001). Conclusion: The CD8+ CTL density and PD-L1 expression are prognostic biomarkers for the survival of patients with CRC.

PD‐L1+ dendritic cells in the tumor microenvironment correlate with good prognosis and CD8+ T cell infiltration in colon cancer

“…One such mechanism is the hijacking of intrinsic immune checkpoint mechanisms, notably the programmed death receptor‐1 (PD‐1) signaling pathway. PD‐ligand‐1 (PD‐L1) and, to a lesser extent, PD‐ligand‐2 (PD‐L2) can be expressed on tumor, immune, endothelial, and muscle cells 7‐10 . Binding of PD‐L1/PD‐L2 to PD‐1, expressed by activated lymphocytes, can attenuate adaptive anti–tumor immune responses 10 .…”

“…This may reflect the different underlying mechanisms of PD‐L1 expression by tumor cells and lymphocytes. Lymphocytes upregulate PD‐L1 expression in response to adaptive immune responses, so higher PD‐L1 expression may be reflective of higher levels of immune cell infiltration 7,9,10 . Whereas, in addition to cytokine‐induced expression, underlying genetic aberrations have been demonstrated to amplify the PD‐L1 gene in tumor cells, leading to constitutive expression of PD‐L1 and, therefore, an association with poor survival outcomes 9,19 .…”

“…(PD-L1) and, to a lesser extent, PD-ligand-2 (PD-L2) can be expressed on tumor, immune, endothelial, and muscle cells. [7][8][9][10] Binding of PD-L1/ PD-L2 to PD-1, expressed by activated lymphocytes, can attenuate adaptive anti-tumor immune responses. 10 PD-L1 expression in tumor specimens is often used to predict response to PD-1/PD-L1 blockade therapy and in many cases, treatment is contingent upon demonstration of tumor-associated PD-L1 expression above a defined threshold using an approved companion diagnostic test.…”

PD‑L1 expression increased by IFN‑γ via JAK2‑STAT1 signaling and predicts a poor survival in colorectal cancer

“…Previous studies have reported that PD-L1 expression on tumor-infiltrating immune cells is correlated with the survival of patients with CRC ( 32 – 34 ). Moreover, the tumor microenvironment in CRC becomes infiltrated with T lymphocytes, which have the potential to activate the JAK/STAT signaling pathway following IFN-γ stimulation ( 35 ).…”

Unripe Black Raspberry (Rubus coreanus Miquel) Extract and Its Constitute, Ellagic Acid Induces T Cell Activation and Antitumor Immunity by Blocking PD-1/PD-L1 Interaction

“…The programmed cell death protein 1 receptor (PD-1), and its ligand programmed death ligand 1 (PD-L1), are one of most extensively studied immune checkpoints [2]. The PD-1 and PD-L1 are major co-inhibitory receptors that involved in T cell-mediated immunity [3]. The recognition between PD-L1 and PD-1 decreases T cell functions including the proliferation and Interleukin (IL)-2 cytokine release in the tumor microenvironment [4].…”