Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Potential role of plasmacytoid dendritic cells for FOXP3+ regulatory T cell development in human colorectal cancer and tumor draining lymph node.

FOXP3(+) regulatory T cells (Tregs) play an important role in the maintenance of tumor immunity tolerance. Compared with conventional myeloid dentritic cells (mDCs), plasmacytoid dendritic cells (pDCs) exhibit poor immunostimulatory ability, and their interaction with T cells often promotes the development of Tregs. The aim of this study was to determine FOXP3(+) Tregs and CD123(+)pDCs infiltration in colorectal cancer and tumor draining lymph node (TDLN), and to evaluate the clinical significance and relationship between pDCs infiltration and Tregs development in the CRC tolerogenic milieu. An immunohistochemical assay was conducted to assess FOXP3(+)Tregs and CD123(+)pDCs infiltration in tumor tissue and in metastatic-free TDLN (mfTDLN) and metastatic TDLN (mTDLN). The results showed that FOXP3(+) Tregs infiltration was more frequent in tumor tissue than in adjacent normal mucosa (P<0.001). FOXP3(+)Tregs infiltration was associated with advanced TNM stage and lymph node metastasis (P<0.01 and P<0.01 for TNM stage and lymph node metastasis, respectively). Different from FOXP3(+)Tregs, CD123(+)pDCs frequencies were lower in most CRC tumor tissues, whereas the positive rate of CD123 expression in CRC was significantly higher than in adjacent normal mucosa tissue (P<0.01). Compared to mfTDLN, mTDLN was significantly enriched in FOXP3(+) Tregs (P<0.01) and increased in pDC/mDC ratio (P<0.01). The statistical analysis demonstrated a significant correlation in both Tregs and pDC/mDC ratio in mTDLN. These results suggest that there are more FOXP3(+) Tregs with a stronger prognostic significance which might promote tumor tolerance, and that CD123(+)pDCs might contribute to Tregs development in the CRC tolerogenic milieu.

FOXP3 and TLR4 protein expression are correlated in non-small cell lung cancer: implications for tumor progression and escape.

NSCLC (non-small cell lung cancer) is the most common type of lung cancer and usually has poor prognosis. FOXP3 in regulatory T cells (Tregs) and toll-like receptor 4 (TLR4) on some tumor cells are known to be important for tumor escape and clinical tumor formation. Since FOXP3 was found recently in some tumor cells, we speculated if lung tumor cells express FOXP3 and then mimic Tregs to promote tumor escape. As TLR4 induces activation of Tregs, we also hypothesized that FOXP3 and TLR4 may have a correlation in NSCLC progression. The expression levels of FOXP3 and TLR4 protein were detected using immunohistochemistry in 53 postoperative specimens of NSCLC patients and in 15 normal lung tissues from excisions of benign lesion. The relationship between protein expression levels and clinical pathology parameters, as well as the relationship between the expression of FOXP3 and TLR4, were analyzed. FOXP3 and TLR4 expression in NSCLC were significantly elevated as compared to normal lung tissue. FOXP3 expression was closely related with lymph node metastasis and TNM staging, whereas TLR4 expression was closely related with tumor differentiation. The Spearman correlation coefficient indicated a significant positive correlation between FOXP3 and TLR4 expression. These results indicate that FOXP3 and TLR4 may coordinate to play a role in tumor escape and subsequent tumor progression.

In situ analysis of FOXP3+ regulatory T cells and myeloid dendritic cells in human colorectal cancer tissue and tumor-draining lymph node.

Forkhead box protein 3 (FOXP3) regulatory T cells (Tregs) are important in the maintenance of tumor immunity tolerance. Myeloid dendritic cells (mDCs) are antigen-presenting cells (APCs) specialized to initiate and regulate immunity. Tregs and mDCs are suspected of influencing the interaction between the tumor and immune system, and thus the course of tumors. However, the implication and interaction of their concurrent infitration in colorectal cancer (CRC) remain unknown. The aim of this study was to determine FOXP3+ Tregs and CD11c+ mDCs infiltration in CRC and tumor-draining lymph node (TDLN) and to explore the clinical and pathological implication of suppressor and effector immune cell subsets. Immunohistochemical assay was conducted to assess FOXP3+ Tregs and CD11c+ mDCs infiltration in tumor tissue and in metastasis-free TDLN (mfTDLN) and metastatic TDLN (mTDLN). The results showed that FOXP3+ Tregs and CD11c+ mDCs infiltration was higher in tumor tissue compared to adjacent normal mucosa (P<0.001). FOXP3+ Tregs infiltration was associated with advanced tumor-node-metastasis (TNM) stage and lymph node metastasis (P<0.001 and P<0.001, for TNM stage and lymph node metastasis, respectively), whereas less CD11c+ mDCs infiltration of tumor in situ was associated with deeper tumor invasion, advanced TNM stages and lymph node metastasis (P<0.05, P<0.001 and P<0.001, for tumor invasion depth, TNM stages and lymph node metastasis, respectively). Compared to mfTDLN, mTDLN was significantly enriched in FOXP3+ Tregs (P<0.001) and reduced in CD11c+ mDCs (P<0.001). The statistical analysis demonstrated no significant correlations in Tregs and mDCs infiltration. These results suggest that more FOXP3+ Tregs and less CD11c+ mDCs infiltration have stronger prognostic significance in CRC. The presence of tumor cells in mTDLN may contribute to a tolerogenic milieu and facilitate the survival of metastatic tumor cells.