cIAP1/2 antagonism eliminates MHC class I negative tumors through T cell-dependent reprogramming of mononuclear phagocytes

Induction of non-canonical NF-kB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We show that induction of non-canonical NF-kB signaling induces T-cell dependent immune responses even in B2M-null tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced cytokines reprogram macrophages to be tumoricidal. In wildtype mice, IAP antagonism reduces tumor burden by increasing phagocytosis of tumor cells. We characterized by RNA-Seq the transcriptional response of macrophages to T-cell produced lymphotoxin (LT) in the presence or absence of the IAP antagonist LCL161. Bone Marrow Derived Macrophages (BMDMs) were incubated for 24 hours with LCL161 plus LTα1β2 (n = 2) or LTα1β2 alone (n = 2) or Vehicle (n = 2).