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

Isabella Lurje,Christoph Roderburg,Raphael Mohr,Wiebke Werner,Frank Tacke,Linda Hammerich

doi:10.3389/fimmu.2021.650486

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.

Highlights

Liver cancer is the fourth leading cause of death worldwide, causing almost 800,000 deaths annually [1, 2]
This review aims to give a comprehensive overview of in situ vaccines for the treatment of Hepatocellular carcinoma (HCC) in the context of the underlying immune dysfunction and immunosuppressive tumor microenvironment (TME)
high mobility group box 1 (HMGB1) is released from damaged cells due to the permeabilization of nuclear and plasma membranes and binds to receptors on immune cells such as TLR2, TLR4 and receptor for advanced glycation endproducts (RAGE) [49], while highmobility group nucleosome binding domain 1 (HMGN1)

Summary

INTRODUCTION

Liver cancer is the fourth leading cause of death worldwide, causing almost 800,000 deaths annually [1, 2]. Several prerequisites for a successful antitumor immune response have been identified: i) The availability of TAAs in a sufficiently immunogenic setting to trigger phagocytosis and activate DCs; ii) an efficient antigen presentation with co-stimulatory signals to successfully crossprime CD8+ cytotoxic T cells; and iii) a cytotoxic T cell response that overcomes inhibitory signals from the tumor and TME This will result in adaptive antitumor responses with local and systemic effects (Figure 1) [22]. Type 1 conventional DCs (cDC1) are capable of cross-presenting extracellular antigens in a MHCIrestricted manner to CD8+ cells [31], a process that, depending on the state of DC maturity and concomitant expression of costimulatory molecules or tolerogenic signals can result either in T cell cross-tolerance or in an efficient T cell cross-priming with ensuing cytotoxic activity [32] The latter makes the cDC1CD8+ T cell interaction essential for tumor recognition and the initiation of antitumor immune responses. HMGB1 is released from damaged cells due to the permeabilization of nuclear and plasma membranes and binds to receptors on immune cells such as TLR2, TLR4 and receptor for advanced glycation endproducts (RAGE) [49], while HMGN1

Immunological Findings

Lenvantinib orally

Findings