Yik Ling Bowie Cheng

All Publications

• Pharmacologic glycoengineering of Fcγ receptor IIIa enhances force-resistant IgG-FcγR interactions and anti-tumor antibody efficacy. Immunity Cheng, B. Y., Centeio, R. M., Chiu, D. K., Kiyohara, C. L., Herzog, E., Dahan, R., Thomas, W. E., Wang, T. T. 2026

  Abstract

  Therapeutic monoclonal antibodies (mAbs) are central to cancer treatment but often show incomplete efficacy. We show that transient pharmacologic inhibition of complex N-glycans in host cells ("glycoengineering") enhances the in vivo activity of multiple depleting mAbs, including mAbs already engineered for heightened potency. In preclinical models, glycoengineering improved α-CD20-mediated tumor clearance and survival through FcγRIIIa- and natural killer (NK) cell-dependent pathways. In B16-F10 melanoma, glycoengineering similarly enhanced anti-CD25 depletion of intratumoral regulatory T cells (Tregs). Notably, glycoengineering produced minimal changes in equilibrium binding affinity but markedly increased the mechanical durability of IgG-FcγRIIIa interactions under physiological shear stress. These results establish antibody effector function as a mechano-immunological process in which IgG-FcγR interactions can be tuned for resilience to physiological forces, thereby moving beyond the current affinity-centric paradigm in mAb engineering. Integrating mechanobiology into therapeutic development may enable mAbs optimized for the dynamic forces of human physiology, which provides a route to enhance next-generation immunotherapies.

  View details for DOI 10.1016/j.immuni.2026.03.028

  View details for PubMedID 42034063

• Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity. Science (New York, N.Y.) Chiu, D. K., Zhang, X., Cheng, B. Y., Liu, Q., Hayashi, K., Yu, B., Lee, R., Zhang, C., An, X., Rajadas, J., Reticker-Flynn, N. E., Rankin, E. B., Engleman, E. G. 2025; 388 (6745): eadr3026

  Abstract

  Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

  View details for DOI 10.1126/science.adr3026

  View details for PubMedID 40273234

• Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease. Immunity Chakraborty, S., Cheng, B. Y., Edwards, D. L., Gonzalez, J. C., Chiu, D. K., Zheng, H., Scallan, C., Guo, X., Tan, G. S., Coffey, G. P., Conley, P. B., Hume, P. S., Janssen, W. J., Byers, D. E., Mudd, P. A., Taubenberger, J., Memoli, M., Davis, M. M., Chua, K. F., Diamond, M. S., Andreakos, E., Khatri, P., Wang, T. T. 2024

  Abstract

  While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor kappaB (NF-kappaB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.

  View details for DOI 10.1016/j.immuni.2024.10.002

  View details for PubMedID 39541970

• Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity. Science translational medicine Chakraborty, S., Gonzalez, J. C., Sievers, B. L., Mallajosyula, V., Chakraborty, S., Dubey, M., Ashraf, U., Cheng, B. Y., Kathale, N., Tran, K. Q., Scallan, C., Sinnott, A., Cassidy, A., Chen, S. T., Gelbart, T., Gao, F., Golan, Y., Ji, X., Kim-Schulze, S., Prahl, M., Gaw, S. L., Gnjatic, S., Marron, T. U., Merad, M., Arunachalam, P. S., Boyd, S. D., Davis, M. M., Holubar, M., Khosla, C., Maecker, H. T., Maldonado, Y., Mellins, E. D., Nadeau, K. C., Pulendran, B., Singh, U., Subramanian, A., Utz, P. J., Sherwood, R., Zhang, S., Jagannathan, P., Tan, G. S., Wang, T. T. 1800: eabm7853

  Abstract

  A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc gamma receptor (FcgammaR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcgammaR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.

  View details for DOI 10.1126/scitranslmed.abm7853

  View details for PubMedID 35040666