In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma

Abstract

Hepatocellular Carcinoma (HCC) is a highly prevalent malignancy that develops in patients with chronic liver diseases and dysregulated systemic and hepatic immunity. The tumor microenvironment (TME) contains tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) and is central to mediating immune evasion and resistance to therapy. The interplay between these cells types often leads to insufficient antigen presentation, preventing effective anti-tumor immune responses. In situ vaccines harness the tumor as the source of antigens and implement sequential immunomodulation to generate systemic and lasting antitumor immunity. Thus, in situ vaccines hold the promise to induce a switch from an immunosuppressive environment where HCC cells evade antigen presentation and suppress T cell responses towards an immunostimulatory environment enriched for activated cytotoxic cells. Pivotal steps of in situ vaccination include the induction of immunogenic cell death of tumor cells, a recruitment of antigen-presenting cells with a focus on dendritic cells, their loading and maturation and a subsequent cross-priming of CD8+ T cells to ensure cytotoxic activity against tumor cells. Several in situ vaccine approaches have been suggested, with vaccine regimens including oncolytic viruses, Flt3L, GM-CSF and TLR agonists. Moreover, combinations with checkpoint inhibitors have been suggested in HCC and other tumor entities. This review will give an overview of various in situ vaccine strategies for HCC, highlighting the potentials and pitfalls of in situ vaccines to treat liver cancer.

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma

“…In addition, emerging studies have proven the importance of tumorinfiltrating lymphocytes in driving immune evasion during HCC progression, including regulatory T cells, tumorassociated macrophages, etc. (49). The exhaustion of follicular helper T cells induced by intra-tumoral PDL1 resulted in the defective B cell function, facilitating the progression of advanced HCC (50).…”

Role of Exosomes in Immunotherapy of Hepatocellular Carcinoma

“…ICIs mainly include monoclonal antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand-programmed cell death ligand 1 (PD-L1), which block these immune checkpoints, thereby promoting the T cell-mediated antitumoral immune responses [ 5 , 6 , 7 , 8 ]. Other immunotherapies, including cancer vaccines and adoptive cell therapy, have also shown great potential for clinical application to treat advanced HCC [ 9 , 10 ]. Nevertheless, numerous HCC patients do not benefit from immunotherapy, which has seriously restricted its application [ 11 , 12 ].…”

Antitumor Effect of Pseudolaric Acid B Involving Regulation of Notch1/Akt Signaling Response in Human Hepatoma Cell In Vitro

“…Liver cancer of more than 905,000 new cases causing 830,000 deaths worldwide annually is regarded as the fourth leading cause of cancer-related death worldwide [ 1 , 2 ]. Among them, hepatocellular carcinoma (HCC) cases account for 90% or more, which is much higher than that of intrahepatic cholangiocarcinoma, liver angiosarcoma, and hepatoblastoma [ 3 , 4 ]. It is noted that 50% or more of new cases of HCC occurs in China, of which approximately 60% are initially diagnosed as the mid or later-stage, showing a 5 year survival rate of 5%–15%, which is lower than 50%–70% of early HCC [ 2 , 5 ].…”