Lecture Report | Professor Jun Wang Shares Twenty Years of Tumor Immunology Research
Recently, the Shanghai Institutes for Biological Sciences invited Professor Jun Wang from the NYU Grossman School of Medicine to present an academic report titled "Probing key immune feedback modulators for next-generation immunotherapies."
During the lecture, Professor Jun Wang systematically reviewed his nearly twenty years of research and major advancements in the field of immunotherapy. From his doctoral research on the hepatotoxicity mechanisms related to the 4-1BB target, to witnessing the clinical breakthrough of PD-1 immunotherapy during his postdoctoral training in the US and establishing a functional screening platform to identify novel immune targets, to independently leading a lab focused on immune checkpoint biology and discovering new regulatory pathways. Prof. Wang's research is consistently driven by a core objective: to identify next-generation transformative therapeutic targets for cancer patients who are unresponsive or resistant to current PD-1 therapies, and to explore the optimal clinical applications of various immune checkpoints in human diseases.
This report centered on the concept of immune feedback regulation recently proposed by Prof. Wang. He systematically introduced the critical role of this mechanism in tumors and autoimmune diseases, alongside the team's research paradigm for discovering novel immunotherapy targets through functional screening strategies.
Prof. Wang first reviewed the evolution of immune checkpoint research. Over the past decade, checkpoint blockades represented by PD-1/PD-L1 have significantly transformed the cancer treatment landscape, yet only a fraction of patients benefit. Unfortunately, beyond PD-1/PD-L1, most immune checkpoints have not demonstrated strong clinical value. Thus, discovering new immune regulatory pathways and elucidating their mechanisms has become a vital direction for driving next-generation immunotherapy. Centered on this goal, Prof. Wang discovered various novel immune regulatory molecules during his postdoctoral research via functional screening. For example, he first discovered that Siglec-15 is an immunosuppressive molecule primarily expressed on tumor-associated macrophages, acting independently of the classic PD-1/PD-L1 pathway, providing a new perspective to explain why some patients are unresponsive to PD-1 therapy. Subsequently, he discovered that FGL1 is a functional ligand for the LAG-3 immune checkpoint, revealing an immune evasion mechanism where tumors suppress T cell function via secreted factors. These studies laid a crucial foundation for understanding the tumor immune regulatory network.
Building upon this foundation, Prof. Wang's lab and collaborators further focused on the mechanisms of immune checkpoint molecules. They found that LAG-3 forms a flexible dimeric structure through its Domain 2 immunoglobulin domain, whereas PD-1 dimerization is mediated by its transmembrane domain. These structural features play a key role in the formation of T cell inhibitory signals. These findings not only deepen the understanding of immune checkpoint signaling mechanisms but also provide important insights for developing new immune modulation strategies. For instance, this mechanism explains why antibodies targeting the membrane-proximal epitope of PD-1 might possess stronger functional activity against autoimmune diseases.
Based on elucidating these mechanisms, Prof. Wang proposed an important theoretical perspective to explain the differences in the role of various immune checkpoints in tumor therapy. He pointed out that the PD-1/PD-L1 pathway essentially constitutes a localized immune negative feedback loop induced by the disease microenvironment. During immune activation, T cells are induced to express the PD-1 receptor, while the ligand PD-L1 can be broadly induced by inflammatory signals on tumor cells, antigen-presenting cells, and stromal cells. This inhibitory signal, which synchronizes with the immune response in time and space, forms a localized immune negative feedback regulatory loop, thereby effectively limiting sustained T cell activation. Prof. Wang pointed out that it is precisely this disease-induced local negative feedback mechanism that makes both PD-1 and PD-L1 highly valuable therapeutic targets for immune regulation; blocking this pathway essentially dismantles the inhibitory feedback formed in the tumor microenvironment, thereby restoring the anti-tumor function of T cells.
In contrast, although LAG-3 is similarly induced after T cell activation, its ligand system is more complex and highly context-dependent. Currently known LAG-3 ligands include MHC-II and FGL1, but the expression of these molecules is not as broadly induced in inflammatory environments as PD-L1. Therefore, the inhibitory role of the LAG-3 pathway in the tumor microenvironment is often more dependent on specific cell types or local conditions, rendering its immunosuppressive effects more "conditional." This characteristic may explain why LAG-3 typically requires combination with PD-1 blockades to produce more noticeable efficacy in tumor immunotherapy.
On the other hand, this characteristic of insufficient or heterogeneous ligand expression also provides new opportunities for the therapeutic application of the LAG-3 pathway in autoimmune diseases. Unlike PD-1, in many inflammatory environments, the PD-1 receptor may already be highly occupied by its endogenous ligands, leaving limited room for further enhancement of this pathway via agonistic antibodies. For LAG-3, however, its inhibitory signal is often not fully utilized. Thus, through engineering strategies, this inhibitory signal can be artificially established or strengthened to achieve selective modulation of autoreactive T cells.
Based on this understanding, the team further revealed the critical role of T cell receptor spatial proximity in LAG-3's suppressive function and engineered the first immune checkpoint mechanism-based Bispecific T cell Suppressor (LAG-3 BiTS). This molecule can selectively inhibit LAG-3-expressing autoreactive T cells, providing a novel strategy for precise immune modulation in autoimmune diseases.
In the latter half of the report, Prof. Wang expanded this concept to broader immune feedback modulators. He noted that the key to immune checkpoint therapy lies not only in the inhibitory receptors themselves but in the immune feedback regulatory networks in which they reside. Understanding these feedback loops induced by the disease microenvironment will help discover new druggable regulatory nodes and guide the design of next-generation immunotherapies.
Revolving around this research direction, the team recently discovered multiple new immune regulatory mechanisms. For example, a membrane-associated MHC-I inhibitory axis discovered in tumor cells can attenuate antigen presentation capabilities by promoting MHC-I molecule degradation, thereby reducing the probability of tumor cells being recognized by CD8⁺ T cells. Additionally, the team identified an inducible myeloid immunosuppressive receptor that plays a crucial regulatory role in tissue immune responses and various disease models. These discoveries indicate that immune regulation exists not only at the classic lymphocyte checkpoint level but also extensively within tissue-level feedback networks mediated by tumor and myeloid cells.
Prof. Wang emphasized in his report that future major breakthroughs in the field of immunotherapy will likely come from the systematic resolution of immune feedback circuits. By integrating functional screening, single-cell sequencing, and spatial transcriptomics, the research team is gradually mapping the immune regulatory landscape in the tumor microenvironment and driving the clinical translation of these original discoveries.
This report demonstrated the developmental trend of immune checkpoint research from single targets to systematic immune feedback regulatory networks, providing a new perspective for understanding tumor immune evasion mechanisms and developing next-generation immunotherapy strategies. Following the report, the attending faculty and students engaged in in-depth discussions with Prof. Wang regarding immune feedback regulatory mechanisms, functional screening strategies, and potential drug targets.