TY - JOUR
T1 - cIAP1/2 antagonism eliminates MHC class I–negative tumors through T cell–dependent reprogramming of mononuclear phagocytes
AU - Roehle, Kevin
AU - Qiang, Li
AU - Ventre, Katherine S.
AU - Heid, Daniel
AU - Ali, Lestat R.
AU - Lenehan, Patrick
AU - Heckler, Max
AU - Crowley, Stephanie J.
AU - Stump, Courtney T.
AU - Ro, Gabrielle
AU - Godicelj, Anže
AU - Bhuiyan, Aladdin M.
AU - Yang, Annan
AU - del Rey, Maria Quiles
AU - Biary, Tamara
AU - Luoma, Adrienne M.
AU - Bruck, Patrick T.
AU - Tegethoff, Jana F.
AU - Nopper, Svenja L.
AU - Li, Jinyang
AU - Byrne, Katelyn T.
AU - Pelletier, Marc
AU - Wucherpfennig, Kai W.
AU - Stanger, Ben Z.
AU - Akin, James J.
AU - Mancias, Joseph D.
AU - Agudo, Judith
AU - Dougan, Michael
AU - Dougan, Stephanie K.
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;
PY - 2021/5/19
Y1 - 2021/5/19
N2 - Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) 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 B (NF-B) signaling. Induction of noncanonical NF-B signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-B signaling induces T cell–dependent immune responses, even in β2-microglobulin (β2M)–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-B 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-γsensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.
AB - Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) 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 B (NF-B) signaling. Induction of noncanonical NF-B signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-B signaling induces T cell–dependent immune responses, even in β2-microglobulin (β2M)–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-B 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-γsensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.
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U2 - 10.1126/scitranslmed.abf5058
DO - 10.1126/scitranslmed.abf5058
M3 - Article
C2 - 34011631
AN - SCOPUS:85106464962
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 594
M1 - eabf5058
ER -