Therapeutics for Leukemia: Targeting Cancer-associated Glycans

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.