TY - JOUR
T1 - High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege
AU - Ager, Casey R.
AU - Boda, Akash
AU - Rajapakshe, Kimal
AU - Lea, Spencer Thomas
AU - DI Francesco, Maria Emilia
AU - Jayaprakash, Priyamvada
AU - Slay, Ravaen B.
AU - Morrow, Brittany
AU - Prasad, Rishika
AU - Dean, Meghan A.
AU - Duffy, Colm R.
AU - Coarfa, Cristian
AU - Jones, Philip
AU - Curran, Michael A.
N1 - Funding Information:
Funding These studies were supported by a Pancreatic Cancer Action Network Translational Research Grant (18-65-CURR). Partial support was also provided by an MD Anderson Sheikh Ahmed Bin Zayed Al Nahyan Grant and by the Department of Defense Peer Reviewed Cancer Research Program Career Development Award CA140792. CRA was supported by NIH TL1 fellowships (TL1TR000369 and TL1TR000371).
Publisher Copyright:
©
PY - 2021/8/2
Y1 - 2021/8/2
N2 - Background Intratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking. Methods Here, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency. Additionally, we leverage orthotopic Kras +/G12D TP53 +/R172H Pdx1-Cre (KPC) derived models of pancreatic adenocarcinoma (PDAC) to determine the capacity for locally administered CDNs to sensitize PDAC to immune checkpoint blockade. We use bioluminescent in vivo imaging and 30-parameter flow cytometry to profile growth kinetics and remodeling of the tumor stroma post-therapy. Results Highly potent synthetic STING agonists repolarize suppressive myeloid populations of human and murine origin in part through inhibition of Myc signaling, metabolic modulation, and antagonism of cell cycle. Surprisingly, high-potency synthetic agonists engage qualitatively unique pathways as compared with natural CDNs. Consistent with our mechanistic observations, we find that intratumoral injection of the highest activity STING agonist, IACS-8803, into orthotopic pancreatic adenocarcinoma lesions unmasks sensitivity to checkpoint blockade immunotherapy. Dimensionality reduction analyses of high parameter flow cytometry data reveals substantial contributions of both myeloid repolarization and T cell activation underlying the in vivo therapeutic benefit of this approach. Conclusions This study defines the molecular basis of STING-mediated myeloid reprogramming, revealing previously unappreciated and qualitatively unique pathways engaged by CDNs of ascending potency during functional repolarization. Furthermore, we demonstrate the potential for high potency CDNs to overcome immunotherapy resistance in an orthotopic, multifocal model of PDAC.
AB - Background Intratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking. Methods Here, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency. Additionally, we leverage orthotopic Kras +/G12D TP53 +/R172H Pdx1-Cre (KPC) derived models of pancreatic adenocarcinoma (PDAC) to determine the capacity for locally administered CDNs to sensitize PDAC to immune checkpoint blockade. We use bioluminescent in vivo imaging and 30-parameter flow cytometry to profile growth kinetics and remodeling of the tumor stroma post-therapy. Results Highly potent synthetic STING agonists repolarize suppressive myeloid populations of human and murine origin in part through inhibition of Myc signaling, metabolic modulation, and antagonism of cell cycle. Surprisingly, high-potency synthetic agonists engage qualitatively unique pathways as compared with natural CDNs. Consistent with our mechanistic observations, we find that intratumoral injection of the highest activity STING agonist, IACS-8803, into orthotopic pancreatic adenocarcinoma lesions unmasks sensitivity to checkpoint blockade immunotherapy. Dimensionality reduction analyses of high parameter flow cytometry data reveals substantial contributions of both myeloid repolarization and T cell activation underlying the in vivo therapeutic benefit of this approach. Conclusions This study defines the molecular basis of STING-mediated myeloid reprogramming, revealing previously unappreciated and qualitatively unique pathways engaged by CDNs of ascending potency during functional repolarization. Furthermore, we demonstrate the potential for high potency CDNs to overcome immunotherapy resistance in an orthotopic, multifocal model of PDAC.
KW - alarmins
KW - immunity
KW - immunotherapy
KW - innate
KW - myeloid-derived suppressor cells
KW - tumor microenvironment
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UR - http://www.scopus.com/inward/citedby.url?scp=85112597010&partnerID=8YFLogxK
U2 - 10.1136/jitc-2021-003246
DO - 10.1136/jitc-2021-003246
M3 - Article
C2 - 34341132
AN - SCOPUS:85112597010
SN - 2051-1426
VL - 9
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 8
M1 - 003246
ER -