Immunotherapy for tumors (Section One)

  • Unlike previous surgical excision, chemotherapy, radiotherapy and gene targeted therapy, cancer immunotherapy is aimed at a patient own immune system to fight cancer. In recent years, monoclonal antibodies against immune checkpoints have created a revolution in clinical oncology, which is an important milestone on the journey of cancer therapy. The Success of checkpoint blockades is slowly driving researchers away from the genetic view of cancer to immune—based approaches. Cancer immunotherapy comprises a variety of treatment approaches: non—specific immune-stimulatory agents, cancer vaccines, adoptive cell transfer and monoclonal antibodies. The pathogenesis of tumor is extremely complicated with its heterogenicity and genetic instability, so that a certain kind of treatment may not be able to achieve the ideal therapeutic effect´╝ÄThus, combination strategies with gene targeted therapy, cytotoxic chemotherapy, and different immunotherapies based on a better understanding about the mechanism of interaction among different classes of therapies may be the direction in the future.

    The immune response produces a complex interaction between the adaptive immune system and the natural immune system. B cells and T cells of the adaptive immune system use their receptors to recognize antigens, and T cells recognize antigen presenting cells (APC) to present antigenic peptides, a major histocompatibility complex (MHC). Molecular complexes, B cells directly recognize antigenic epitopes, adaptive immunity is highly specific and has immune memory: natural immunity is non-specific immunity, and patterns expressed by phagocytic cells, natural killer cells (NK), etc. The recognition of receptor-derived receptors (PRRs) identifies pathogen-associated molecular patterns shared by microorganisms and their products, such as lipopolysaccharide, peptidoglycan, and mannose, regulating the initiation, strength, and type of response of specific immune responses.

    Dendritic cells (DCs) are a class of non-mononuclear phagocytic cells, which are important bonds between natural and adaptive immunity and are the most powerful APCs known in the human body. The production of anti-tumor immunity depends on the DC to capture the tumor antigen, process it intracellularly, and then present the antigen information to the immature T cells in the lymphoid tissue to activate it, thereby activating the specific immune response of the body. Activated T cells release cytokines and further stimulate T cell division, proliferation and maturation. A part of mature T cells differentiates into memory T cells to retain antigenic memory and rapidly respond to re-invasion of antigens, and most of them differentiate into effector cells with immune effects, such as regulatory T cells that produce cytokine-regulated immune responses. Killer T cells that target and kill foreign cells, as well as effector T cells that stimulate B lymphocyte proliferation and antibody production.

    Tumor antigens are the core of tumor immunity, and the recognition of tumor antigens is the theoretical and material basis of specific active immunotherapy. Melanoma antigen (MAGE) was first discovered in 1991. 1 Since the human tumor immunological rejection, the tumor antigens identified so far are mainly classified into the following categories: 1 embryonic antigen or tissue-specific antigen: such as carcinoembryonic antigen, prostate specific antigen, glycoprotein 100, malignant MAGE family antigen and Human "epidermal growth factor receptor-2" (Her-2/neu) antigen expressed in breast cancer and ovarian cancer cells; 2 mutation or fusion gene product: such as Ras oncogene product P21 , the mutant tumor suppressor gene product P53, fusion gene products formed by different chromosomal breaks, PML-RARcc, bcr-abl, AML1-ETO, etc.; 8 virus-derived antigens: such as human papilloma virus (HPV vaccine development) antigen, EB virus antigen, Hepatitis B virus antigen, etc; MHC non-limiting antigen, the above tumor antigens require the presentation of MHC molecules.

     The identification and selection of early tumor antigens mostly focus on tumor cell consensus antigens, which has the advantage of being suitable for a wider range of cancer patients. The disadvantage is that these shared antigens also have some expression in normal tissues or embryo tissues, which may lead to antigen peptides. The immune tolerance of a high affinity effect of an MHC-T cell antigen receptor limits the therapeutic effect. On the other hand, due to its great heterogeneity and genetic instability, tumors have long been subjected to immune selection pressure in the body environment, and only those tumor cells that are not antigenic or antigenic are able to survive. Therefore, tumor antigens are generally characterized by low immunogenicity. How to enhance the antigenicity of tumor cells is the key to effective immunotherapy.

    To be continued in Section Two…