Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site

Abstract

Stimulator of IFN genes (STING) spontaneously contributes to anti-tumor immunity by inducing type I interferons (IFNs) following sensing of tumor-derived genomic DNAs in the tumor-bearing host. Although direct injection of STING ligands such as cyclic diguanylate monophosphate (c-di-GMP) and cyclic [G(2',5')pA(3',5')p] (cGAMP) into the tumor microenvironment exerts anti-tumor effects through strong induction of type I IFNs and activation of innate and adaptive immunity, the precise events caused by STING in the tumor microenvironment remain to be elucidated. We describe here our finding that a CD45 CD11b Ly6C cell subset transiently accumulated in mouse tumor microenvironment of 4T1 breast cancer, squamous cell carcinomas, CT26 colon cancer, or B16F10 melanoma tissue after intratumoral injection of cGAMP. The accumulated cells displayed a macrophage (M ) phenotype since the cells were positive for F4/80 and MHC class II and negative for Ly6G. Intratumoral cGAMP treatment did not induce Mφ accumulation in STING-deficient mice. Depletion of CD8 T cell using anti-CD8 mAb impaired the anti-tumor effects of cGAMP treatment. Depletion of the Mφ using clodronate liposomes impaired the anti-tumor effects of cGAMP treatment. Functional analysis indicated that the STING-triggered tumor-migrating Mφ exhibited phagocytic activity, production of tumor necrosis factor alpha TNFα), and high expression levels of T cell-recruiting chemokines, Cxcl10 and Cxcl11, IFN-induced molecules, MX dynamin-like GTPase 1 (Mx1) and 2'-5' oligoadenylate synthetase-like 1 (Oasl1), nitric oxide synthase 2 (Nos2), and interferon beta 1 (Ifnb1). These results indicate that the STING-triggered tumor-migrating Mφ participate in the anti-tumor effects of STING-activating compounds.

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

“…reported to display increased phagocytosis and other markers of macrophage activation; they also recruit new macrophages which serve a phagocytic role in the TME [41][42][43][44] . Consistent with these observations we confirmed that HMDMs transfected with c-di-AMP showed increased phagocytosis and exhibited elongated dendrites compared to mock-transfected populations ( Fig.…”

Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery

“…Although this result should be interpreted carefully due to low number of patients in our subgroup analysis, it may be pointed out that similar findings were observed by Aljabery et al in bladder cancer (Aljabery et al 2017). A protective effect of TAMs has been demonstrated both in vitro and in vivo (Ohkuri et al 2017). Fidler (1988) showed that activation of macrophages eliminated cancer cells and reduced metastases, but this mechanism was limited by the ratio of macrophages in relation to target cancer cells (Fidler 1988).…”

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…Unfortunately, not much research has focused on CXCL11 in BC. The stimulation of IFN genes (STING) triggers macrophage production of TNFα and high expression levels of the T cell-recruiting chemokines CXCL10 and CXCL11 [50]. …”