Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

Xiuting Liu; Graham D. Hogg; Chong Zuo; Nicholas C. Borcherding; John M. Baer; Varintra E. Lander; Liang I. Kang; Brett L. Knolhoff; Faiz Ahmad; Robin E. Osterhout; Anna V. Galkin; Jean Marie Bruey; Laura L. Carter; Cedric Mpoy; Kiran R. Vij; Ryan C. Fields; Julie K. Schwarz; Haeseong Park; Vineet Gupta; David G. DeNardo

doi:10.1016/j.ccell.2023.04.018

Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

Xiuting Liu, Graham D. Hogg, Chong Zuo, Nicholas C. Borcherding, John M. Baer, Varintra E. Lander, Liang I. Kang, Brett L. Knolhoff, Faiz Ahmad, Robin E. Osterhout, Anna V. Galkin, Jean Marie Bruey, Laura L. Carter, Cedric Mpoy, Kiran R. Vij, Ryan C. Fields, Julie K. Schwarz, Haeseong Park, Vineet Gupta, David G. DeNardo

Research output: Contribution to journal › Article › peer-review

Abstract

Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.

Original language	English (US)
Pages (from-to)	1073-1090.e12
Journal	Cancer Cell
Volume	41
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2023.04.018
State	Published - Jun 12 2023
Externally published	Yes

Keywords

CD11b
NF-κB
STING
immunotherapy
pancreatic cancer
tumor-associated macrophages

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2023.04.018

Cite this

Liu, X., Hogg, G. D., Zuo, C., Borcherding, N. C., Baer, J. M., Lander, V. E., Kang, L. I., Knolhoff, B. L., Ahmad, F., Osterhout, R. E., Galkin, A. V., Bruey, J. M., Carter, L. L., Mpoy, C., Vij, K. R., Fields, R. C., Schwarz, J. K., Park, H., Gupta, V., & DeNardo, D. G. (2023). Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity. Cancer Cell, 41(6), 1073-1090.e12. https://doi.org/10.1016/j.ccell.2023.04.018

Liu, X, Hogg, GD, Zuo, C, Borcherding, NC, Baer, JM, Lander, VE, Kang, LI, Knolhoff, BL, Ahmad, F, Osterhout, RE, Galkin, AV, Bruey, JM, Carter, LL, Mpoy, C, Vij, KR, Fields, RC, Schwarz, JK, Park, H, Gupta, V & DeNardo, DG 2023, 'Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity', Cancer Cell, vol. 41, no. 6, pp. 1073-1090.e12. https://doi.org/10.1016/j.ccell.2023.04.018

@article{f5d19d3267d444d09185b0990a24052a,

title = "Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity",

abstract = "Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.",

keywords = "CD11b, NF-κB, STING, immunotherapy, pancreatic cancer, tumor-associated macrophages",

author = "Xiuting Liu and Hogg, {Graham D.} and Chong Zuo and Borcherding, {Nicholas C.} and Baer, {John M.} and Lander, {Varintra E.} and Kang, {Liang I.} and Knolhoff, {Brett L.} and Faiz Ahmad and Osterhout, {Robin E.} and Galkin, {Anna V.} and Bruey, {Jean Marie} and Carter, {Laura L.} and Cedric Mpoy and Vij, {Kiran R.} and Fields, {Ryan C.} and Schwarz, {Julie K.} and Haeseong Park and Vineet Gupta and DeNardo, {David G.}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = jun,

day = "12",

doi = "10.1016/j.ccell.2023.04.018",

language = "English (US)",

volume = "41",

pages = "1073--1090.e12",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

AU - Liu, Xiuting

AU - Hogg, Graham D.

AU - Zuo, Chong

AU - Borcherding, Nicholas C.

AU - Baer, John M.

AU - Lander, Varintra E.

AU - Kang, Liang I.

AU - Knolhoff, Brett L.

AU - Ahmad, Faiz

AU - Osterhout, Robin E.

AU - Galkin, Anna V.

AU - Bruey, Jean Marie

AU - Carter, Laura L.

AU - Mpoy, Cedric

AU - Vij, Kiran R.

AU - Fields, Ryan C.

AU - Schwarz, Julie K.

AU - Park, Haeseong

AU - Gupta, Vineet

AU - DeNardo, David G.

PY - 2023/6/12

Y1 - 2023/6/12

N2 - Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.

AB - Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.

KW - CD11b

KW - NF-κB

KW - STING

KW - immunotherapy

KW - pancreatic cancer

KW - tumor-associated macrophages

UR - http://www.scopus.com/inward/record.url?scp=85161516274&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85161516274&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2023.04.018

DO - 10.1016/j.ccell.2023.04.018

M3 - Article

C2 - 37236195

AN - SCOPUS:85161516274

SN - 1535-6108

VL - 41

SP - 1073-1090.e12

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this