| First Author | Roehle K | Year | 2021 |
| Journal | Sci Transl Med | Volume | 13 |
| Issue | 594 | PubMed ID | 34011631 |
| Mgi Jnum | J:308275 | Mgi Id | MGI:6728683 |
| Doi | 10.1126/scitranslmed.abf5058 | Citation | Roehle K, et al. (2021) cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes. Sci Transl Med 13(594) |
| abstractText | Loss of major histocompatibility complex (MHC) class I and interferon-gamma (IFN-gamma) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor kappaB (NF-kappaB) signaling. Induction of noncanonical NF-kappaB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-kappaB signaling induces T cell-dependent immune responses, even in beta2-microglobulin (beta2M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell-expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-kappaB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-gamma sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors. |
