Scientist Apeximmune Therapeutics South San Francisco, California, United States
Disclosure(s):
Julie Huang: No relevant disclosure to display
Introduction/Rationale: Immune checkpoint inhibitors (ICI) have revolutionized solid cancer treatment, achieving remarkable responses in some patients by reinvigorating the immune system to target tumors. However, most patients do not respond to ICIs, and uncovering adaptive resistance mechanisms and other immune regulators remains a significant unmet need. Here, we identify the phospholipase PLA2G2D (G2D) as a potent suppressor of innate and adaptive immunity that contributes to anti-PD-1 resistance and represents a promising immuno-oncology target.
Methods: We used syngeneic tumor models with G2D⁻/⁻, wild-type, and G2D-humanized mice to assess tumor growth and anti-PD-1 response. Immune profiling was performed by flow cytometry, and G2D expression in human tumors was examined by IHC. Human T-cell activation, myeloid differentiation, phagocytosis, and mixed lymphocyte reaction (MLR) assays defined G2D function. Function-blocking monoclonal antibodies were tested in vitro and in vivo.
Results: Primarily expressed by macrophages and dendritic cells (DCs), G2D deficiency in mice reduced syngeneic tumor growth and increased responsiveness to anti-PD-1 therapy. This corresponded with increased CD8+ T cells and cDCs and reduced numbers of immunosuppressive macrophages and regulatory T cells in the TME. G2D inhibited human T cell activation, hindered macrophage and DC differentiation, and reduced macrophage phagocytosis and MLR. These immunosuppressive effects are independent of G2D’s enzymatic activity, revealing a previously unrecognized mechanism. G2D expression is elevated across many human tumor types and robustly induced by cytokines triggered by T cell activation and anti-PD-1 treatment. Function-blocking anti-PLA2G2D antibodies reversed G2D-mediated immunosuppressive functions, diminished tumor growth, and enhanced anti-PD-1 efficacy.
Conclusion: Thus, G2D is a key driver of ICI resistance and a novel immunotherapy target for restoring antitumor immunity, particularly for patients resistant to checkpoint inhibition.
