The inception of cancer immunotherapy could be traced back to the 19^th century when the 'Father of Cancer Immunotherapy', William Coley, successfully led spontaneous regression of tumors by developing erysipelas with the injection of Coley's toxins into cancer patients. Different from cytotoxic chemotherapy, cancer immunotherapy allows targeted therapies, which fight against cancer by exploiting the effector mechanisms of the immune system. Current therapeutic strategies have put more emphasis on coordinating the adaptive immune responses and anti-cancer immunotherapies, but these therapeutics often cause resistance and associated severe toxicities. Therefore, it's increasingly necessary to find alternative therapeutics to adaptive immunity-based immunotherapy, in the process of which the contributions of the innate immune effectors to anti-tumor immunity are growingly recognized.

Hazard of Existing immunotherapies for Leukemia

Immunotherapies are a promising option for treating leukemia compared with modern chemotherapy regimens that have many side effects. Cancer immunotherapies usually induce cancer remission in a long term by leveraging components of the immune system, in which antibodies have been taken as the best candidates for cancer immunotherapy use due to less off-target toxicities. Currently, three categories of immunotherapies, including antibody-drug conjugates (ADCs), bispecific T-cell receptor-engaging (BITE) antibodies, and CAR-T cells are approved for the treatment of relapsed/refractory (R/R) acute leukemias. But these therapeutics for leukemia are greatly limited by resistance, toxicity, and applicability. Another shortcoming of existing immunotherapies is the incapability of eradicating cancer stem cells (CSCs).

Glycans in Cancer

Glycans are part of the immune system's components that can distinguish self from danger. However, cancer cells can make use of the total set of glycans in a biological species to adapt to and escape from the selection pressure exerted by the immune system. This process is called aberrant glycosylation and universally exists in all tumor cells, producing immunogenic glycans that are generally known as tumor-associated carbohydrate antigens (TACAs) or cancer-associated glycans.

Cancer-associated glycans takes an important part in cancer cell signaling, tumor cell dissociation and invasion, cell-matrix interactions, angiogenesis, metastasis and immune modulation, so from cancer-associated glycans researchers can identify that cancer cells have acquired cancer hallmark capabilities. The hallmarks of aberrant glycosylation in leukemia and other cancer cells include sustaining proliferative signaling, evading growth suppressors, deregulating cellular energy, resisting cell death, enabling replicative immortality, activating invasion and metastasis, inducing angiogenesis, genome instability, and mutation, tumor promoting inflammation, and avoiding immune destruction. Moreover, it's proven that aberrant glycosylation is related to tumor initiation, progression, and metastasis, so it could be a new hallmark of cancer development.

Targeting Glycans in Leukemia Therapy

Researchers noticed that lectins can preferentially bind to carbohydrates, highlighting the significance of lectin-glycan interactions in the living system. Lectins have become one of the best candidates for the detection, isolation, and characterization of glycoconjugates, as well as for drug delivery to the site of action due to their ability to bind specific sugar residues in glycoproteins and glycolipid complexes. What's more, lectins can also be applied to distinguish malignant tumor cells from normal cells by recognizing modified glycan structures that are mainly expressed on the surface of tumor cells.

Different from adaptive immune resistance that makes it possible for cancer cells to evade tumor-specific T-cell responses, the innate immune lectins as alternatives can specifically distinguish self from non-self cells and work as crucial defenders without replying on adaptive immunity for pathogen clearance. Considering that expression change of cell-surface glycans caused by the malignant cells is an intrinsic target for lectin recognition, the glycosylation landscape of leukemia and the clinical significance of lectins binding to leukemic blasts have long been an interest to researchers. Thus, the lectin pathway of recognizing cancer's aberrant glycans makes it a canonical component of the innate immune system, which can be exploited in targeting cancer-associated glycans as a therapeutic strategy in leukemia, as well as other cancer immunotherapies.

Bacteria are covered by polysaccharides at the outer surface in the form of capsules, glycoproteins, or glycolipids. Such a bacterial sugar coat constitutes the principal antigens in most pathogenic bacteria and plays an important role in host-pathogen interactions. With more understanding of polysaccharide biosynthesis and its interplay with polymer modification and synthesis, scientists have recognized the research potential of polysaccharides in developing novel antibacterial strategies and novel applications like epidemiological markers.

Bacterial polysaccharides mainly are carbohydrates like capsular polysaccharides (CPS) and lipopolysaccharides (LPS). Capsular polysaccharides are highly-hydrated homo- or hetero-polymers that are composed of repeating sugar units joined by glycosidic linkages. They usually are inserted into the cell surface of bacteria by covalent attachments to either phospholipid or lipid-A molecules. Lipopolysaccharide, on the contrary, is a membrane component characteristic of Gram-negative bacteria consisting of lipid A, core-oligosaccharide, and O-polysaccharide (or O-antigen) joined by a covalent bond. With a series of advanced technologies, including chemical degradation techniques, nuclear magnetic resonance spectroscopy, and mass spectrometry techniques, researchers now can comprehensively carry out structural characterization and analysis of bacterial polysaccharides and understand their functions.

CPS usually constitutes the outermost layer of the cell and gets involved in mediating interactions between bacteria and the environment, for which polysaccharide capsules are implied as important virulence factors for several bacterial pathogens. Moreover, CPS can protect bacteria from phagocytosis if the pathogen is attacked by innate immune responses. Capsular polysaccharides prevent the activation of phagocytosis by decreasing antibody opsonization and masking ligands for phagocytic cell attachment. Therefore, polysaccharides antibodies as biomarkers have become the research hotspot in the field of disease diagnosis and treatment. Researchers at the Queensland University of Technology have successfully characterized the genomic loci in Acinetobacter baumannii that are responsible for cell-surface polysaccharide synthesis and have proven them to be effective epidemiological markers to track A. baumannii.

Lipopolysaccharides are large molecules localized in the outer layer of the bacterial membrane and populate much of the cell surface. LPS can establish a permeability barrier, protecting bacteria from toxic molecules such as antibiotics and bile salts. In addition to being a key component of the cell envelope, LPS also contributes to host-pathogen interactions with the innate immune system. Bacterial adaptive changes, including modulation of LPS synthesis during chronic infection, could protect disease by preventing phagocytosis and adhesion to epithelial cells with O-antigen lipopolysaccharide or enhancing host immune response evasion with a production of less immunogenic lipid A, etc. In some cases, the immune response against the bacterial polysaccharide could be too dramatic to be toxic to the host, which confers protection against the disease in some depth.

Polysaccharides could also be found in fungi and yeast in the form of glucans, chitin, and mannans, playing a major role in the cell wall structure. Current research on fungal polysaccharides mainly aims at identifying influential factors for their biological activity and elucidating their interactive role in various chemical medicine. The biological activities of fungal polysaccharides are shown to influence anti-tumor, anti-microbial, immune-stimulation or immunomodulatory activity, nutritional component, and hypoglycemic activity.

With more understanding of the structure of various polysaccharides, details about the mechanism of action of polysaccharides in different systems are being revealed. Polysaccharides of bacteria and fungi will share more extensive applications in diagnostics and therapeutics.

The complement system, or complement cascade, is regarded as a portion of the innate immune system and may appear 6-7 million years earlier than adaptive immunity. Recent studies have shown that the complement system can get involved in the communication of multiple cells and regulating immune responses, working as a bridge between the innate and adaptive immune responses.

Main Tasks of the Complement System

The complement system plays an important role not only in defending infection but also in the development of autoimmune diseases. The core function of the complement system is to lyse cells, bacteria, and viruses, as well as to initiate phagocytosis by opsonization. What’s more, it exerts influence in triggering inflammation by engaging with immune system cells.

To be straightforward, the complement system is expected to take these functions:

• Mark the invading pathogens by opsonin that promotes phagocytosis.
• Enhance the generation of inflammatory signaling agents (e.g. histamine) and capillary permeability to attract macrophages and neutrophils.
• Attack and rupture the wall of pathogens with membrane attack complex (MAC).

How Does the Complement System Work?

The complement system consists of a variety of proteins and protein fragments that are synthesized by the liver and circulate in the blood as inactive precursors (known as zymogens). Zymogens need to cleavage and become active enzymes for cytolytic and bactericidal activity.

The activation of the complement system may be triggered by antigen-antibody complex, lipopolysaccharide, mannosans, peptidoglycan, etc. Stimulated proteases in the system will cleave specific proteins to release cytokines, further inducing an amplifying cascade of cleavages.

There are three different pathways involved in the activation of the complement system.

• Classical pathway is initiated by the combination of C1q and the classical pathway activator (antigen-antibody complex). And later sequential classic complementactivation will form a membrane attack complex (MAC), making the target cell swell and rupture to death because the osmotic pressure cannot be maintained.
• Alternative pathway starts from the component C3b binding to factor B. It’s independent of the immune response and exerts an important anti-infective effect in the early stage of bacterial infection when no specific antibodies are produced.
• Lectin complement pathwayis activated when mannose-binding lectin (MBL) or ficolin binds to the mannose residues of pathogens based on the pathogen-associated molecular patterns (PAMPs). Similar to the classical pathway, it will later form MAC for opsonization, phagocytosis, and lysis of target microorganisms.

Complement System Research and Development

Studies show that though the complement system takes a key part in defense against pathogens and host homeostasis, the possible unfavorable results cannot be overlooked. When the complement system is regulating immune responses with specific signals, excessive or insufficient activation of the system may cause damages to healthy host cells or tissues.

As for the double-edged functions of the complement system, more and more complement therapeutics are developed, including serine protease inhibitors, soluble complement regulators, therapeutic antibodies, complement component inhibitors, and anaphylatoxin receptor antagonists.

Meanwhile, many life science solution providers get into complement antibody development, serine protease inhibitors development, complement-directed drug discovery, commercial complement product manufacturing, etc. in response to complement research.

Up to now, the complement therapeutic research has been undergoing a highly successful and inspiring period, and numerous complement-based drugs are discovered to treat diseases such as autoimmune disease, nephropathy, osteology, genetic disease, infection, neurology, inflammatory disease, ophthalmology, and cardiovascular disease.