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Combinatorial Immunotherapeutic Strategies in Liver Cancer

ABSTRACT: Combinatorial Immunotherapeutic Strategies in Liver Cancer

PROVIDER: PRJNA1257769 | ENA |

REPOSITORIES: ENA

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Combinatorial Immunotherapeutic Strategies in Liver Cancer

Project description:Background: Immune checkpoint inhibitors combined with antiangiogenic therapy has become the standard of care for advanced hepatocellular carcinoma, albeit with limited therapeutic benefit. Our previous studies demonstrated the immunomodulatory and antitumor effects of polyIC, a synthetic double-stranded RNA. Here, we compared the efficacy of anti-programmed death ligand 1 (?PD-L1) plus polyIC versus ?PD-L1 plus anti-vascular endothelial growth factor (?VEGF) in primary liver tumor models.Conclusion: This preclinical study identifies polyIC as a better enhancer of ?PD-L1 efficacy than ?VEGF in liver cancer, providing a novel strategy for improving immunotherapy outcomes. Further clinical investigation is warranted.

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Project description:Background: Cancer testis antigens (CTAs) are an extensive gene family with a unique expression pattern restricted to testis tissues, but aberrantly high expressed in a variety of cancer tissues. In view of this, CTAs are typically considered as efficient biomarkers and targets of immunotherapy. However, limited information is available regarding CTAs as immunotherapeutic targets for gastric cancer (GC) patients. Herein, we evaluated the expression levels of CTAs in both Eastern and Western GC patients and elucidate the expression pattern and functions of a novel CTAs.

2022-08-09 | GSE210662 | GEO

Isolation and identification of patient-derived liver cancer stem cells and development of personalized treatment strategies

Project description:Liver cancer is a devastating disease characterized by its molecular complexity and the insidious behavior of liver cancer stem cells (LCSCs), which drive the metastasis and recurrence. However, the heterogeneity of molecular markers of LCSCs has hindered the development of effective methods to isolate them. This study introduced a pioneering approach to isolate and culture LCSCs from primary tumor tissues, leveraging mouse embryonic fibroblasts (MEFs) as a feeder cell to provide the niche in conjunction with using defined medium, which stands in stark contrast to traditional techniques, and promised to revolutionize our understanding of LCSCs. Total seventeen cell strains were directly isolated from 24 patients’ tissues without sorting, seven of which could be maintained long-term culture as colony growth on MEFs, which is unique characteristics of stem cells. Cloned cells formed a round packed morphology on MEFs and could be cryopreserved and re-cultured. Even 10 of cloned cells could form xenografts of human liver cancers in immunodeficient mice, indicating high tumorigenicity. Thus, cloned cells could be designated as liver cancer stem cells. Our further investigation found that reported putative liver cancer stem cell markers were all expressed in cloned cells, and stemness of cancer stem cells could well maintained under our developed culture conditions when compared to those under traditional suspension conditions. Furthermore, our findings revealed a distinct molecular landscape within hepatocellular carcinomas (HCCs), pinpointing a C2 subtype with profound implications for personalized medicine and the development of targeted therapies. By illuminating the unique responses of this subtype to chemotherapeutic agents, our research not only advances the frontiers of liver cancer biology but also charts a course for more effective, patient-specific treatment strategies.

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BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Project description:Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCII-lo IL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24 + CD44 – CD40 – B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1 hi IL18 hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.

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