In the 21st century, a series of factors such as environmental pollution, dietary changes, and mental stress have led to an increase in the incidence of cancer. Tumors have become diseases that seriously endanger human health and involve social and economic problems. So, can the tumor be conquered? Everything in the world is justified, and tumors are no exception. Everything in the world is in harmony, and tumors are no exception. The process of formation and change of things, knowing the process of formation and change of things, understands the weaknesses of things, and knows the way to overcome this. So, what is the way to control the tumor?
For many years, humans have used chemotherapy, radiotherapy, surgery and other methods to treat tumors. Although effective, they have not solved the tumor problem fundamentally. “The bell must be tied to the bell.” The tumor grows out of the body itself, and it depends on itself to solve the tumor. The answer has been found, and solving the tumor problem depends on its own immune system. The human immune system is inherently anti-tumor, but during the long-term formation of tumors, tumor cells have evolved a variety of immune escape and immune attack resistance mechanisms to avoid being cleared by the immune system. By blocking the immune escape of the tumor by a certain means or relieving the resistance of the tumor to the immune attack, the effect of enhancing the immune system of the body to kill the tumor can be achieved, which is tumor immunotherapy.
In 1891, William Coley, a doctor at the New York Hospital in the United States, directly injected bacterial lysate into the tumor site of a tumor patient, and achieved efficacy in some patients, opening the first step in tumor immunotherapy. In the early 20th century, it was envisaged that there might be antigenic components in tumor tissue that are different from normal tissues, which may be used to prepare tumor vaccines or antisera (anti-tumor antigen-containing antibodies in serum) for active or passive immunization. To achieve the purpose of cancer prevention and treatment. These ideas opened up experimental studies of tumor immunology and tumor immunotherapy. On this basis, two Australian immunologists, Burnet and Thomas, proposed the theory of tumor immunosurveillance in 1957, which believed that the body’s immune system can recognize and kill tumor cells. Due to the lack of experimental evidence, the theory of tumor immune surveillance has caused much controversy. Later, in the mass-produced immunodeficient nude mice, no increase in tumor incidence was observed, and it was concluded that the tumor immunosurveillance theory was incorrect, leading to clouding of tumor immunity and tumor immunotherapy. In the late 20th century, the advent of monoclonal antibody technology and gene knockout technology and its application enabled people to block some important immune molecules (interferon, interleukin-12, etc.) or knock them out in mice. In this case, tumor growth is significantly accelerated, confirming that the tumor is immunologically monitored in the body. Further, in the late 1990s, the discovery of dendritic cells (DC) paved the basic theoretical framework for tumor immunity: DCs enter the tumor tissue, capture the tumor antigen, leave the tumor site, and enter the lymph nodes near the tumor. The tumor antigen is presented on the surface for T cell recognition. After the T cell recognizes the tumor antigen, it rapidly activates and proliferates into tumor-specific T cells, which leave the lymph node and enter the tumor site to kill the tumor cells. The establishment of the theoretical framework of tumor immunity has greatly promoted the research of tumor immunology theory and clinical trial of tumor immunotherapy, but it was not until 2010 that the FDA approved the Provenge, a DC vaccine for prostate cancer, that it officially opened the tumor immunotherapy. The curtain. The 2011 Nobel Prize in Physiology or Medicine was awarded to the founder of DC, Ralf Steinman, which became a turning point in tumor immunity and tumor immunotherapy. At the end of 2013, Science magazine listed tumor immunotherapy as the top of the top ten scientific and technological progress of the year. The era of tumor immunotherapy comes; in 2018, the Nobel Prize in Physiology or Medicine was awarded to American immunologist James. Allison and Japanese immunologist Tasuku Honjo, in recognition of their contribution to tumor immunotherapy, established the mainstream of tumor immunotherapy. Correspondingly, a large number of tumor immunotherapy drugs or methods were approved, including the approval of the antibody class Pembrolizumab and Nivolumab for PD-1 in 2014, the approval of the oncolytic virus T-Vec drug in 2015, and the approval for treatment in 2016. The market for PD-L1 antibody Durvalumab for melanoma and lung cancer was launched, and the first CAR-T cell drug Kymriah (tisagenlecleucel) for childhood and adult acute lymphoblastic leukemia was approved for marketing in 2017.
In the face of the current situation, tumor immunotherapy seems to be able to overcome the tumor, but this is not the case. Tumors, as extremely complex systemic and systemic diseases, are extremely difficult to fully understand. Tumor immunotherapy as a new treatment for cancer, its strategy and theory still need to be improved and improved, but also need to be combined with non-immunotherapy. In short, the road to tumor immunotherapy is still rugged, but it has been placed on high hopes and become a weapon to overcome tumors. This article provides a general overview of the 2018 cancer immunology research hotspot.
Tumor immune checkpoint breakthrough
PD-1 and CTLA-4 have become the star of immunological checkpoint research, and the Nobel Prize in Physiology or Medicine in 2018 has pushed it to the wave of research. However, is there any other checkpoint molecule that can be used for tumor immunotherapy? On December 20, 2018, “Cell” published “Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3” online. The study found that the main ligand of the immunosuppressive molecule LAG-3 is fibrinogen-like protein 1. (FGL1). The expression of LAG-3 on the surface of T cells has been found to be immunosuppressive for many years, but its ligand has been unclear. In this study, the secreted protein FGL1 was screened by the genome-scale receptor array system, which confirmed that FGL1 is a ligand of LAG-3 and exerts immunosuppressive effects by tumor utilization. More significantly, high levels of FGL1 in the serum of patients with non-small cell lung cancer or melanoma treated with PD1 antibodies tend to have a worse prognosis, suggesting that for patients with PD1 antibody resistance, blocking the FGL1-LAG-3 pathway may become Potential treatment options. In addition, inhibition of the FGL1-LAG-3 pathway alone can exert anti-tumor effects, and combined with PD1 monoclonal antibody treatment has a better anti-tumor effect. This study suggests that the FGL1-LAG-3 pathway may be a new battlefield for tumor immunotherapy that is independent of known immune escape pathways (eg, PDL1-PD-1).
In addition to the immune checkpoint for T cells, Tian Zhigang, a professor at the University of Science and Technology of China, conducted a study on the NK cell immune checkpoint, and in June 2018, published in the journal Nature Immunology, Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion. And elicits potent anti-tumor immunity, identified TIGIT as an NK cell immune checkpoint, not CTLA-4 and PD-1. Further studies have found that blocking TIGIT reverses the inhibition state of NK cells, allowing them to exert anti-tumor responses while enhancing anti-tumor memory responses. This study points to the possibility of checkpoint therapy for NK cells. As an important group of natural immune cells, NK cells have not been prominent in their research on anti-tumor effects. The above research work will play a driving role.
New tumor-reactive T cell depletion markers were found
When T cells enter the tumor site, they will gradually deplete and lose the ability to kill tumor cells. Blocking the inhibition of PD-1 can only partially reverse the depletion. T cell depletion describes a functional state in which T cells are located, meaning that T cells gradually lose their effector function and reactivity under repeated stimulation by antigens such as viral antigens or tumor antigens. Depletion of T cells is characterized by decreased secretion of cytokines IL-2, IFN-gamma and TNF, up-regulation of inhibitory receptor expression, and decreased release of cytotoxic effector molecules perforin and granzyme. The surface markers of T cell depletion mainly include PD-1, CTLA-4, TIM-3, LAG-3 and TIGIT. Reversing depleted T cells is a hot spot in current tumor immunotherapy research. In June 2018, Harvard Medical School’s research team published an article in the journal Nature, “Induction and transcriptional regulation of the co-inhibitory gene module in T cells,” by analyzing RNA and protein expression at mouse single-cell levels. Spectrum, found new T cell depletion markers: PROCR and PDPN. At the same time, it was also identified that PRDM1 and c-MAF are transcription factors that regulate these molecules. The discovery of these new markers broadens people’s understanding of T cell depletion and provides new targets for tumor immunotherapy.
For T cell depletion at the tumor site, they were initially thought to belong to a tumor-reactive T cell population rather than a bystander T cell at the tumor site. However, in May 2018, the research paper “Bystander CD8 + T cells are abundant and phenotypically distinct in human tumour infiltrates ” published by Nature showed that although most of the T cells in the tumor site are bystander T cells, they are also depleted. appear. In December 2018, the article “Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers” published by Nature Medicine further reinforces the concept. In this study, 90% of tumor sites are found in human ovarian and colon cancers. T cells do not recognize tumor cells and belong to bystander T cells. This raises a major scientific issue, namely how to alter bystander T cells and give them the ability to recognize tumor cells.
A new subgroup of tumor immunosuppressive cells was discovered
In addition to the molecular level of tumor immunology research, new tumor immunosuppression-related cells are also being discovered. In March 2018, “Cell” magazine published the “Tumor-induced generation of splenic erythroblast-like Ter-cells promotes tumor progression” by the team of Cao Xuetao of Nankai University. This study found non-leukocyte groups that promote tumor progression. Cells: Ter-119 + CD45 – CD71 + cells. This tumor immune-related suppressor cell is activated by TGF-β released from the primary tumor to activate Smad3 in the spleen, and produces artemin to promote tumor progression. Further blocking of artemin or its receptor GFRα3 can inhibit tumor progression. In October of the same year, the article “Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells” published by Zhu Bo team of the Third Military Medical University in Nature Medicine showed that “Ter-119 + CD71 + cells” can induce late stage. Tumor patients were immunosuppressed and anaemic, except that the group of cells identified by the team belonged to the “CD45 + ” leukocyte group. “CD45 + Ter-119 + CD71 + for extramedullary hematopoiesis under tumor inductionThe cells aggregate in the spleen and inhibit the anti-tumor immune response of CD8 T cells by secreting ROS, and increase the number of Treg and MDSC to further induce immunosuppression. The use of ROS inhibitors can relieve the immunosuppressive effect of this group of cells. The successive discovery of two groups of immunosuppressive cells further broadens people’s understanding of the whole body’s immune environment and provides new directions and targets for future tumor immunotherapy.
New strategies for tumor immunotherapy gradually emerge
Even if all immunosuppressive signals are blocked, all tumor immunosuppressive cells are cleared as much as possible, and perhaps not all tumor cells can be killed. There are still many unknowns about the tumor itself. Certain cytokines released by the immune system can kill tumor cells, inhibit tumor angiogenesis, and play a role in immune surveillance, but unexpectedly, these cytokines can induce tumor cells that have not been killed to enter a dormant state. Therefore, the elimination of tumor dormancy, combined with tumor immunotherapy may be the key to killing all tumor cells. In 2017, Huang Bo team published an article in the “Nature Communications” “Blockade of IDO-kynurenine-AhRmetabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells”, revealing the anti-tumor factor IFN-γ induced tumor regenerative cells (tumor-repopulating cells, TRCs) into the mechanism of dormancy. In February 2018, the team published “STAT3/p53 pathway activation disrupts IFN-β-induced dormancy intumor-repopulating cells” in the Journal of Clinical Investigation. It was found that the antiviral factor IFN-β can induce tumor regenerative cells more strongly. Go to sleep. More recently, the team published “Fibrin stiffness mediates dormancy of tumor-repopulating cells via a Cdc42-driven Tet2 epigenetic program” in Cancer Research in May 2018, which analyzes the hard physical microenvironment from a new perspective. Genetically regulated tumor regenerative cell dormancy. A series of reports on tumor dormancy suggest that immune and physical factors affect tumor cell dormancy, which may be a new direction of tumor immunotherapy.
Although the immunosuppressive signaling molecule PD-1 blocking antibody is widely used clinically, the molecular mechanism of how it is overexpressed in tumor-specific T cells is unclear. In March 2018, “Cancer Cell” published the research results of the Yellow Wave team “Tumor repopulating cells induce PD-1 expression in CD8 + T cells by transferring kynurenine and AhR activation”. The study found that activated T cells not only kill The tumor-regenerating cells with dryness are instead acted to up-regulate the expression of PD-1, thereby revealing the molecular mechanism by which tumor T cells up-regulate PD-1 expression. This laid a theoretical foundation for the development of new PD-1 signaling pathway inhibitors and the development of new tumor immunotherapy strategies.
In short, with the deepening of research, human beings are uncovering the true face of tumor immunity. It is believed that in the near future, more cancer patients will benefit from tumor immunotherapy.