EP4 Antagonism by E7046 diminishes Myeloid immunosuppression and synergizes with Treg-reducing IL-2-Diphtheria toxin fusion protein in restoring anti-tumor immunity

• Published in: Oncoimmunology Vol. 6; no. 8; p. e1338239
• Main Authors: Albu, Diana I., Wang, Zichun, Huang, Kuan-Chun, Wu, Jiayi, Twine, Natalie, Leacu, Sarah, Ingersoll, Christy, Parent, Lana, Lee, Winnie, Liu, Diana, Wright-Michaud, Renee, Kumar, Namita, Kuznetsov, Galina, Chen, Qian, Zheng, Wanjun, Nomoto, Kenichi, Woodall-Jappe, Mary, Bao, Xingfeng
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03-08-2017; Taylor & Francis Group
• Subjects: Anti-tumor immunity; EP4 antagonism; myeloid cells; Original Research; PGE; pge2; T regulatory cells; PGE2; myeloid cells; T regulatory cells; EP4 antagonism; Anti-tumor immunity
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2017.1338239

Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting alternatively activated tumor associated macrophages (M2TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE
2
), an arachidonic acid pathway metabolite and mediator of chronic inflammation, has emerged as a powerful immunosuppressor in the TME through engagement with one or more of its 4 receptors (EP1-EP4). We have developed E7046, an orally bioavailable EP4-specific antagonist and show here that E7046 has specific and potent inhibitory activity on PGE
2
-mediated pro-tumor myeloid cell differentiation and activation. E7046 treatment reduced the growth or even rejected established tumors in vivo in a manner dependent on both myeloid and CD8
+
T cells. Furthermore, co-administration of E7046 and E7777, an IL-2-diphtheria toxin fusion protein that preferentially kills Tregs, synergistically disrupted the myeloid and Treg immunosuppressive networks, resulting in effective and durable anti-tumor immune responses in mouse tumor models. In the TME, E7046 and E7777 markedly increased ratios of CD8
+
granzymeB
+
cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic inflammation phenotype into acute inflammation, shown by substantial induction of STAT1/IRF-1 and IFNγ-controlled genes. Notably, E7046 also showed synergistic anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been reported to diminish intratumoral Tregs. Our studies thus reveal a specific myeloid cell differentiation-modifying activity by EP4 blockade and a novel combination of E7046 and E7777 as a means to synergistically mitigate both myeloid and Treg-derived immunosuppression for cancer treatment in preclinical models.