Novartis Institutes for Biomedical Research, Cambridge, MA, USA
Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits.In exploratory clinical studies, we demonstrated that vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF followed by antibody blockade of CTLA-4 accomplished clinically significant tumor destruction with minimal toxicity in some stage IV metastatic melanoma and advanced ovarian carcinoma patients.The extent of tumor necrosis in post-treatment biopsies was linearly related to the natural logarithm of the ratio of infiltrating CD8+ effector T cells to FoxP3+ Tregs, and was associated with the induction of a potent antibody response to tumor cell surface and secreted factors. The presence of abundant Treg infiltrates in patients who failed to respond to therapy suggests that further Treg inhibition might increase the proportion of patients who benefit.
Notwithstanding the ability of GM-CSF to enhance protective immunity, our analysis of GM-CSF deficient mice delineated a critical role for the cytokine in immunoregulation through the maintenance of Treg homeostasis.GM-CSF is required for the expression of the phosphatidylserine binding protein MFG-E8 in antigen presenting cells, whereas the uptake of apoptotic cells by phagocyte-derived MFG-E8 maintains peripheral Treg activity through a mechanism that involves TGF-beta and CCL22.The pharmacologic inhibition of MFG-E8 function through genetic or engineering-based approaches blocks Treg induction, which intensifies vaccine-induced responses, leading to the regression of established tumors in mice.
A more detailed understanding of the determinants underlying GM-CSF induced immunostimulation versus immunoregulation is required to further optimize the application of the cytokine for cancer therapy.Ongoing work exploring genetic and small molecule based approaches to interrogate GM-CSF function will be discussed.
Credits: None available.
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