In the inducible oncogenic KRAS mouse model of PDAC, Gulhati et al. showed that high levels of immunosuppressive myeloid cells contributed to T cell dysfunction and checkpoint blockade resistance. Agonist 4-1BB and antagonist LAG3 (alone or in combination) increased antitumor immunity and survival. This was associated with increased antitumor T cells, more clonal and diverse T cells, reduced number and function of immunosuppressive myeloid cells, and increased antigen presentation by myeloid cells. The addition of a CXCR1/2 inhibitor targeting MDSCs resulted in durable complete responses and resistance to rechallenge. Similar profiles were observed in data from patients with PDAC.
Contributed by Lauren Hitchings
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.