The role of the immunoescape in colorectal cancer liver metastasis

Abstract

The expression of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) indicate the efficacy of anti-PD-1/PD-L1 therapy in colorectal cancer (CRC), but are less useful for monitoring the efficacy of therapy of CRC liver metastasis (CRLM). This study investigated the effects of immune molecules on the prognosis of CRLM. We enrolled 71 patients with CRLM who underwent curative resection for CRC. We used immunohistochemistry to analyze the expression of PD-1, PD-L1, indoleamine-pyrrole 2,3-dioxygenase (IDO), and CD163 (a marker of tumor-associated macrophages [TAMs]) in metastatic tumors. The immune molecules PD-1, PD-L1, IDO, and TAMs were expressed in 32.3%, 47.8%, 45.0%, and 47.9% of metastatic CRC samples, respectively. The 5-year overall survival rates associated with immune molecule-positive groups were significantly better than in the negative groups (PD-1: 87.7% vs 53.2%, p = 0.023; PD-L1: 82.4% vs 42.3%, p = 0.007; IDO: 80.7% vs 43.5%, p = 0.007; TAMs: 82.6% vs 48.0%, p = 0.005). Multivariate analysis revealed PD-1 expression (p = 0.032, hazard ratio: 0.19), IDO expression (p = 0.049, hazard ratio: 0.37), and tumor differentiation (p<0.001, hazard ratio: 0.02) as independent prognostic indicators. PD-1 and TAMs in metastases were associated with less aggressive features such as smaller tumors. Furthermore, TAMs positively and significantly correlated with PD-1 expression (p = 0.011), PD-L1 expression (p = 0.024), and tended to correlate with IDO expression (p = 0.078). PD-1, PD-L1, IDO, and TAMs in CRLM were associated with less aggressive features and better prognosis of patients with CRC, indicating adaptive antitumor immunity vs immune tolerance. These molecules may therefore serve as prognostic markers for CRLM.

Role of stromal PD-L1 expression in colorectal liver metastasis

“…1a and 1b). The IHC score for PD-L1 expression in both stromal and tumor cells was calculated by the sum scoring of staining intensity and the distribution as described previously [12]. Brie y, staining intensity was scored as: 0, no staining; 1, weak; 2, moderate; 3, strong staining.…”

“…Distribution was scored as follows, 0, ≤ 5%; 1, 6-25%; 2, 26-50%; 3, 51-75%; 4, 76-100%. Final score of more than 3 was de ned as positive for PD-L1 expression in stromal cells [25,26] and tumor cells [12,27]. PD-1 expression was positive when > 40% of mononuclear cells in tumor tissues stained at ×400 magni cation (Fig.…”

“…Formalin-xed, para n-embedded tissues were prepared for immunohistochemistry as described previously [12]. The para n-embedded samples were serially cut into 5-µm-thick sections that were dewaxed in xylene, rehydrated, and rinsed in a series of decreasing alcohol concentrations.…”

“…PD-1 expression was positive when > 40% of mononuclear cells in tumor tissues stained at ×400 magni cation (Fig. 1c) [12,28]. PD-1 positivity was de ned as more than 40% of mononuclear cells were stained in the tumor at high power eld of ×400.…”

“…Furthermore, the e cacy of immune blockade for liver metastasis of various cancers including CRC is unsatisfactory [9][10][11]. We previously reported the characteristics of immune markers in CRLM including PD-1, PD-L1, tumor-associated macrophages and indoleamine-pyrrole 2,3-dioxygenase [12]. Expression of these immunosuppressive proteins correlates to favorable survival and diminished tumor aggressiveness of CRLM.…”