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Thursday March 07, 2024

Congratulations to Di Yu, 2021 ASI Career Advancement Awardee - Ada category

We warmly congratulate
Di Yu
recipient of the 2021 ASI Career Advancement Award - Gordon Ada category

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Advancing the careers of ASI Members

 

I'm deeply appreciative of the support from the ASI Gordon Ada Career Advancement Award, which facilitated my attendance at the Seventh CRI-ENCI-AACR International Cancer Immunotherapy Conference (CICON23, 20-23 September, Milan, Italy) and the Keystone symposium “T and B Cell Collaboration in Germinal Centres and Beyond” (1-4 October, Whistler, Canada). This support also provided an opportunity to visit Prof Luis Graca at the Instituto de Medicina Molecular, Lisbon, Portugal, between these conferences.

My name is Di Yu, and I serve as a Professor of Immunology, leading the "Systems and Translational T-cell Immunology Lab" (STTIL) at the Frazer Institute, University of Queensland. I also hold the position of Chair in Paediatric Immunology and Director of the Ian Frazer Centre for Children’s Immunotherapy Research at the Children’s Health Research Centre, UQ. These roles demand continuous research to understand the complex regulation of T cell function in immune responses and to translate this knowledge into innovative and precise therapies for severe diseases in children. The travel supported by the ASI Gordon Ada Senior Travel Award has been immensely beneficial for both aspects.

The Keystone symposium covered a wide range of topics from basic immunobiology of germinal centre function and follicular helper T cell differentiation to the regulation of T-B interactions and their relevance to diseases like immunodeficiency, infection, cancer, and autoimmune conditions.

Significant findings were shared. Memory B cells and antibody-secreting B cells are the major products from germinal centres (GCs) so how these cells are selected and participate in immune responses are of great interest. Prof Oliver Bannard from University of Oxford reported that, in influenza A infection, antibody-secreting B cells from GCs are diverse in their affinities. This challenges the prevailing view that antibody-secreting B cells are preferentially selected from high-affinity GC B cell clones, which was mostly established from clonally restricted GC B cells in the immunisation models using simple antigens. The selection of antibody-secreting cells with low affinity might facilitate diverse serum antibody responses. This study was recently published in Cell (DOI:https://doi.org/10.1016/j.cell.2023.10.022). Assoc. Prof Gabriel Victora from Rockefeller University used various genetic tools to study how naïve and memory B cells participate recall GC responses. He reported that recall GCs primarily composed of naïve B cells, yet recall antibody production is predominantly from memory B cells. This phenomenon is attributed to suppression by pre-existing antibodies, suggesting a model where antibody feedback directs recall B cells towards new epitopes (https://doi.org/10.1101/2023.12.15.571936).

Dr Pamela Schwartzberg from NIAID at NIH gave the plenary talk on the topic of PI3Kδ in Tfh cell function. She previously generated hyperactive PI3Kδ p110δ^E1020K mice to recapitulate major features of the human activated PI3Kδ syndrome (APDS), a human primary immunodeficiency characterised by lymphoproliferation, respiratory infections and inefficient responses to vaccines (https://doi.org/10.1038/s41590-018-0182-3). In the following study, she found Ras GTPase-activating protein 3 (RASA3) acts downstream of the PI3Kδ signalling and as a key suppressor of LFA-1 activation in T cells, influencing T cell migration, lymph node trafficking, and immune response effectiveness (https://doi.org/10.1126/scisignal.abl9169).

Tertiary lymphoid structures (TLS) are often present within tumours and correlate with better prognosis. These structures are composed of various immune cells like B cells, T cells, dendritic cells, and follicular dendritic cells, organised in a way that somewhat mirrors the organization of secondary lymphoid organs. Dr Ziv Shulman from Weizmann Institute of Science demonstrates that somatic hypermutations enhance the antitumor reactivity of antibodies targeting autoantigens in ovarian carcinoma, with patient-derived tumour cells often coated with IgG. These findings reveal that tumour-reactive autoantibodies in the tumour microenvironment may either be naturally occurring or evolve through antigen-driven selection, offering diagnostic and therapeutic potential in cancer (https://doi.org/10.1016/j.cell.2022.02.012).

Compared to the Keystone symposium, the CICON23 conference was more translation-oriented.

Prof. James Allison from the MD Anderson Cancer Center at the University of Texas gave the ENCI-AIRC Lecture. He focused on the CTLA4 blockade immunotherapy and explained its difference from the PD-1/PD-L1 blockade immunotherapy. Anti-CTLA4 therapy has significant effects on CD4⁺ T cells and induces the expansion of an ICOS⁺ Th1-like CD4⁺ effector population (https://doi.org/10.1016%2Fj.cell.2017.07.024). In addition to immune checkpoint blockade immunotherapies, Dr Özlem Türeci, co-founder of BioNTech talked about mRNA-based cancer vaccine. RNA-lipoplexes (RNA-LPX) cancer vaccine can effectively target dendritic cells and trigger immune responses that include IFN-α release and T-cell activation. This approach has shown promise in early-phase clinical trials for melanoma (https://doi.org/10.1038/nature18300). Besides cancer immunotherapies targeting T cells, Prof. Eric Vivier from Paris Saclay Cancer Cluster demonstrated a very intriguing innovation of trifunctional NK cell engagers (NKCEs), which targeting two activating receptors, NKp46 and CD16a, on NK cells and a tumour antigen on cancer cells (https://doi.org/10.1016/j.cell.2019.04.041). CD123-NKCE that targets CD123 on acute myeloid leukemia (AML) shows its efficacy in mouse models and safety in nonhuman primates, along with prolonged pharmacodynamic effects, supporting its clinical development for AML treatment (https://doi.org/10.1038/s41587-022-01626-2).

The CICON23 conference also underscored the importance of basic mechanistic research for advancing cancer immunotherapies. Tumour-reactive CD8⁺ T cells in cancer patients often become dysfunctional and unable to stop tumour growth, with adoptive T cell transfer (ACT) therapies showing limited efficacy due to rapid loss of CD8⁺ T cell effector function. Using preclinical cancer mouse models, Assoc. Prof. Andrea Schietinger from Memorial Sloan Kettering Cancer Center has revealed that the formation of triads involving tumour-specific CD4⁺ T cells, and antigen-presenting cells, in addition to CD8⁺ T cells, is crucial for enhancing CD8⁺ T cell cytotoxicity and effectively eliminating cancer cells, offering a new strategy for improving ACT outcomes (https://doi.org/10.1101/2023.07.03.547423). Tumour microenvironment is not only about immune cells but also about tumours.  CD8⁺ T cells, particularly terminally exhausted T cells, face metabolic challenges due to competition for glucose with highly glycolytic tumour cells and the acidification of the extracellular space by lactic acid. Assoc. Prof. Greg Delgoffe from University of Pittsburgh studies metabolic barriers to effective cancer immunotherapy. He reveals that Tex cells express MCT11, a transporter facilitating lactate uptake, and can utilise lactate as an alternative energy source. Blocking MCT11, either genetically or through antibody therapy, enhanced the anti-tumour efficacy of CD8⁺ T cells, suggesting that targeting MCT11 could be a promising therapeutic strategy to reinvigorate exhausted T cells in cancer treatment (http://dx.doi.org/10.1136/jitc-2023-SITC2023.1347).

These experiences have enriched my research and collaborative endeavours, significantly contributing to the advancement of immunotherapy.

Author: Di Yu

Disclaimer: The views expressed are those of the author/s and do not necessarily reflect the official policy or position of ASI