Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy.

Background: Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies, yet biopsies can only provide baseline information. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest. Design: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 35 patients with different advanced gastrointestinal tumors were enrolled in a phase 1 trial of a PD-1 inhibitor, IBI308. The CTC numeration and the PD-L1 expression levels were analyzed. Results: Prior the treatment of IBI308, 97% (34/35) patients had CTCs, ranging from1 to 70 (median 7). 74% (26/35) had PD-L1positive CTCs, and 60% (21/35) had at least one PD-L1high CTCs. The disease control (DC) rate in PD-L1high patients (48%) is much higher than the others (14%). The group with at least 20% abundance of PD-L1high CTCs had even higher DC rate of 64% (9/14), with only 14% DC rate for the rest (3/21). We also observed that the count changes of total CTC, PD-L1postive CTC and PD-L1high CTC correlate quite well with disease outcome (P<0.001, P = 0.002 and 0.007, respectively). In addition, the abundance of PD-L1high CTCs at baseline had predicative significance for progression free survival (PFS). Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of CTC could indicate the therapeutic response at early time.

The correlation of KAI1, Slug and vasculogenic mimicry in the prediction of metastasis and prognosis in colorectal carcinoma.

KAI1 and the epithelial-mesenchymal transition regulator Slug, as well as vasculogenic mimicry (VM), play a significant role in the process of metastasis and prognosis in many human cancers. This study investigated the relationship of KAI1, Slug and VM and their connection with clinicopathological features, metastasis and their prognostic value in colorectal carcinoma (CRC). Immunohistochemistry was performed to analyze the expression of KAI, Slug, VM, E-cadherin (E-cad) and vimentin in 134 human CRC and corresponding normal mucosal tissues. The results showed that the protein expressions of KAI1, Slug and VM in tumor tissues were significantly different from adjacent normal mucosal tissues. The expression of KAI1 was negatively related, while the expressions of Slug and VM are positively related with differentiation, lymph node metastasis, distant metastasis and TNM stage. KAI1 was negatively related, while VM was positively related with invasion. The expression of KAI1 showed a negative correlation with Slug and VM. Moreover, the expression of Slug was positively associated with VM. A Kaplan-Meier analysis showed that the expression of Slug and VM was negatively and KAI1 expression was positively correlated with overall survival. Low KAI1 expression and high Slug and VM expression showed a poorer prognosis in CRC. Multivariate Cox regression analysis showed that the expression of KAI1, Slug, VM and TNM stage were independent predictors of OS in CRC. The expression of KAI1, Slug and VM was correlated with metastasis and prognosis. These findings suggest that KAI1, Slug and VM can be novel therapeutic targets to predict metastasis and prognosis in CRC patients.

Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma.

Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in regulating the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating immune cells (TILs) in the tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Archival formalin-fixed, paraffin-embedded ESCC samples from treatment-naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy were collected between 2004 and 2014. Expression of PD-L1 in ESCC tumor specimens was assessed by immunohistochemistry (IHC), and the degree of TIL infiltration was evaluated by examining hematoxylin and eosin-stained (H&E) specimens. PD-L1+ as defined as ≥1% of tumor cell membranes showing ≥1+ intensity. In 428 patients, specimens from 341 (79.7%) were PD-L1+. In the definitive treatment group (patients who received curative esophagectomy or definitive [chemo-]radiation therapy), PD-L1 positivity was associated with a significantly shorter DFS and OS. In the palliative chemotherapy group exhibited, neither PFS nor OS correlated significantly with PD-L1 expression. PD-L1 expression was positively associated with TIL density. In 17 paired tumor tissues collected before and after treatment, an increase in PD-L1 expression was associated with disease progression, whereas a decrease in PD-L1 expression was associated with response to chemotherapy or disease control. So, PD-L1 expression was associated with a significantly worse prognosis in patients with ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.

[A preliminary study of the inhibitive efficacy of iodized linoleic acid and its fluorodeoxyuridine ester in hepatocellular cancer].

OBJECTIVE: To explore the potential of iodized linoleic acid (ILA) and its 5-fluoro-deoxyuridine ester (IFU) to inhibit hepatocellular carcinoma (HCC) cells in vitro and tumors in vivo. METHODS: ILA and its constituent component IFU were chemically synthesized, purified, and confirmed by 1H-NMR. The HCC cell lines, QGY-7703 (5-fluorouracil (5-FU) treatment sensitive) and SMMC-7721 (5-FU resistant), were treated with ILA, IFU, 5-FU, or traditional lipiodol for 72 hours. Survival rates of the treated cells were assessed by the methyl thiazolyl tetrazolium method, and used to calculate the IC50 and IC90. In addition, thirty nude mice were subcutaneously inoculated with SMMC-7721 cells and randomly divided two weeks later into four treatment groups (n = 6 each) for intra-tumoral injection of ILA, IFU, 5-FU, lipiodol or DMSO (controls). The rate of tumor inhibition (RTI) was calculated for each group at week 4 after treatment. RESULTS: For the cultured SMMC-7721 cells, the inhibitory concentrations for ILA, IFU, and 5-FU were: IC50: 134.38 mumol/L, 17.55 mumol/L, and 7.38 mumol/L; IC90: 192.88 mumol/L, 97.63 mumol/L, and more than 200 mumol/L. For the cultured QGY-7703 cells, the inhibitory concentrations for ILA, IFU, and 5-FU were: IC50: 109.55 mumol/L, 44.79 mumol/L, and 98.06 mumol/L; IC90: all, more than 200 mumol/L. In both cell types, the IC50 of lipiodol was more than 400 mumol/L. Compared with the RTI of the control mice (100%), the RTI of ILA-treated mice was 31.9% (t = 2.37, P less than 0.05), of IFU-treated mice was 56.9% (t = 4.91, P less than 0.01), and of 5-FU-treated mice was 31.0% (t = 2.59, P less than 0.05). The RTI of IFU was significantly stronger than that of either ILA or 5-FU (P less than 0.05). The lipiodol treatment showed no inhibition effect on tumors (P more than 0.05). CONCLUSION: ILA and IFU can effectively inhibit the growth of HCC cells in vitro and tumors in vivo. Furthermore, IFU outperforms ILA in inhibiting HCC growth.