Primary liver cancer (PLC), including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), and other rare tumors, is the third leading cause of cancer-related mortality. Of all primary liver cancer, HCC is the most common type. Evidence has accumulated that the tumor microenvironment (TME) plays a key role in fostering or restraining tumor development. The tumor microenvironment (TME), which includes molecular, cellular, extracellular matrix(ECM), and vascular signaling pathways, is a complex ecosystem. The interaction between the tumor microenvironment and cancer cells can enhance the malignant properties of tumors, including proliferation, angiogenesis, metastasis, and therapy resistance. In addition, the tumor microenvironment can also lead to abnormal angiogenesis and promote immunosuppression. HCC has been resistant to targeted therapy and immunotherapy. Therefore, further study of the tumor microenvironment of HCC may be helpful for the development of therapeutic methods for HCC.

It is well established that the tumor microenvironment(TME) plays a pivotal role in tumor initiation, progression and therapeutic resistance by creating a dynamic interaction with cancer cells. TME is comprised of extracellular matrix (ECM), growth factors, nutrients, blood and lymphatic vessels, and non-cancer stromal cells, which serve as a sustained niche for cancer cells to proliferate and metastasize. Notably, various cellular components in TME, including endothelial cells, fibroblasts, pericytes, adipocytes, immune cells, cancer stem cells, and vasculature, could promote tumor’s immune evasion and growth.

This volume evaluates the clinical patterns of resistance to sorafenib, the impact of trial design in the second-line setting and the current gold standard to define radiological resistance; describes the molecular mechanisms responsible for treatment resistance in HCC patients, including components of the immune system and tumor microenvironment; determines the role of the cancer stem cell phenotype in resistance; reviews the experimental models to study resistance; and addresses new approaches to overcome resistance to sorafenib, using successful examples from other malignancies.

This book addresses the biological processes relevant to the immune phenotypes of cancer and their significance for immune responsiveness, based on the premise that malignant cells manipulate their surroundings through an evolutionary process that is controlled by interactions with innate immune sensors as well as the adaptive recognition of self/non-self. Checkpoint inhibitor therapy is now an accepted new form of cancer treatment. Other immuno-oncology approaches, such as adoptive cell therapy and metabolic inhibitors, have also shown promising results for specific indications. Immune resistance is common, however, limiting the efficacy of immunotherapy in many common cancer types. The reasons for such resistance are diverse and peculiar to the immune landscapes of individual cancers, and to the treatment modality used. Accordingly, approaches to circumvent resistance need to take into account context-specific genetic, biological and environmental factors that may affect the cancer immune cycle, and which can best be understood by studying the target tissue and correlated systemic immune markers. Understanding the major requirements for the evolutionary process governing human cancer growth in the immune-competent host will guide effective therapeutic choices that are tailored to the biology of individual cancers.

In this book we provide insights into liver – cancer and immunology. Experts in the field provide an overview over fundamental immunological questions in liver cancer and tumorimmunology, which form the base for immune based approaches in HCC, which gain increasing interest in the community due to first promising results obtained in early clinical trials. Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death in the United States. Treatment options are limited. Viral hepatitis is one of the major risk factors for HCC, which represents a typical “inflammation-induced” cancer. Immune-based treatment approaches have revolutionized oncology in recent years. Various treatment strategies have received FDA approval including dendritic cell vaccination, for prostate cancer as well as immune checkpoint inhibition targeting the CTLA4 or the PD1/PDL1 axis in melanoma, lung, and kidney cancer. Additionally, cell based therapies (adoptive T cell therapy, CAR T cells and TCR transduced T cells) have demonstrated significant efficacy in patients with B cell malignancies and melanoma. Immune checkpoint inhibitors in particular have generated enormous excitement across the entire field of oncology, providing a significant benefit to a minority of patients.