SF2523: Dual PI3K/BRD4 inhibitor blocks tumor immunosuppression and promotes adaptive immune responses in cancer

Shweta Joshi, Alok R. Singh, Kevin X. Liu, Timothy V. Pham, Muamera Zulcic, Dylan Skola, Hyun Bae Chun, Christopher K. Glass, Guillermo A. Morales, Joseph R. Garlich, Donald L. Durden

Research output: Contribution to journalArticle

Abstract

Macrophages (MΘs) are key immune infiltrates in solid tumors and serve as major drivers behind tumor growth, immune suppression, and inhibition of adaptive immune responses in the tumor microenvironment (TME). Bromodomain and extraterminal (BET) protein, BRD4, which binds to acetylated lysine on histone tails, has recently been reported to promote gene transcription of proinflammatory cytokines but has rarely been explored for its role in IL4- driven MΘ transcriptional programming and MΘ-mediated immunosuppression in the TME. Herein, we report that BET bromodomain inhibitor, JQ1, blocks association of BRD4 with promoters of arginase and other IL4-driven MΘ genes, which promote immunosuppression in TME. Pharmacologic inhibition of BRD4 using JQ1 and/or PI3K using dual PI3K/BRD4 inhibitor SF2523 (previously reported by our group as a potent inhibitor to block tumor growth and metastasis in various cancer models) suppresses tumor growth in syngeneic and spontaneous murine cancer models; reduces infiltration of myeloid-derived suppressor cells; blocks polarization of immunosuppressive MΘs; restores CD8+ T-cell activity; and stimulates antitumor immune responses. Finally, our results suggest that BRD4 regulates the immunosuppressive myeloid TME, and BET inhibitors and dual PI3K/BRD4 inhibitors are therapeutic strategies for cancers driven by the MΘ-dependent immunosuppressive TME.

Original languageEnglish (US)
Pages (from-to)1036-1044
Number of pages9
JournalMolecular cancer therapeutics
Volume18
Issue number6
DOIs
StatePublished - Jan 1 2019

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Adaptive Immunity
Phosphatidylinositol 3-Kinases
Immunosuppression
Tumor Microenvironment
Immunosuppressive Agents
Neoplasms
Interleukin-4
Growth
Macrophages
Arginase
Histones
Genes
Lysine
Cytokines
Neoplasm Metastasis
T-Lymphocytes
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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SF2523 : Dual PI3K/BRD4 inhibitor blocks tumor immunosuppression and promotes adaptive immune responses in cancer. / Joshi, Shweta; Singh, Alok R.; Liu, Kevin X.; Pham, Timothy V.; Zulcic, Muamera; Skola, Dylan; Chun, Hyun Bae; Glass, Christopher K.; Morales, Guillermo A.; Garlich, Joseph R.; Durden, Donald L.

In: Molecular cancer therapeutics, Vol. 18, No. 6, 01.01.2019, p. 1036-1044.

Research output: Contribution to journalArticle

Joshi, S, Singh, AR, Liu, KX, Pham, TV, Zulcic, M, Skola, D, Chun, HB, Glass, CK, Morales, GA, Garlich, JR & Durden, DL 2019, 'SF2523: Dual PI3K/BRD4 inhibitor blocks tumor immunosuppression and promotes adaptive immune responses in cancer', Molecular cancer therapeutics, vol. 18, no. 6, pp. 1036-1044. https://doi.org/10.1158/1535-7163.MCT-18-1206
Joshi, Shweta ; Singh, Alok R. ; Liu, Kevin X. ; Pham, Timothy V. ; Zulcic, Muamera ; Skola, Dylan ; Chun, Hyun Bae ; Glass, Christopher K. ; Morales, Guillermo A. ; Garlich, Joseph R. ; Durden, Donald L. / SF2523 : Dual PI3K/BRD4 inhibitor blocks tumor immunosuppression and promotes adaptive immune responses in cancer. In: Molecular cancer therapeutics. 2019 ; Vol. 18, No. 6. pp. 1036-1044.
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