STING activation normalizes the intraperitoneal vascular-immune microenvironment and suppresses peritoneal carcinomatosis of colon cancer

Abstract

BackgroundPeritoneal carcinomatosis is a fatal clinical presentation of colon cancer, characterized by unresponsiveness to conventional anticancer therapies, including immune checkpoint inhibitors. Here, we elucidated the immune-evasion mechanisms during the peritoneal carcinomatosis of colon cancer and developed a novel immunotherapy by activating the stimulator of interferon genes (STING) pathway.MethodsWe generated a syngeneic peritoneal carcinomatosis model of colon cancer. Mice were intraperitoneally treated with either STING agonist (MIW815, also known as ADU-S100) or PD-1 blockade or both. The tumor microenvironment was comprehensively analyzed using multiplexed immunofluorescence imaging, flow cytometry, and NanoString immune profiling.ResultsIntraperitoneal colon cancer cells induce a massive influx of immunosuppressive M2-like macrophages, upregulate immune checkpoints, and impair effector T cell functions during peritoneal dissemination; these collectively create a highly angiogenic and immunosuppressive milieu that is resistant to anti-PD-1 monotherapy. Intraperitoneal administration of a STING agonist suppressed aberrant angiogenesis, increased pericyte coverage, and normalized tumor vessels, thereby facilitating the infiltration of activated CD8+ T cells into peritoneal tumor nodules. Moreover, STING activation reprogramed tumor-associated macrophages toward the M1 phenotype. STING activation converted immunologically cold peritoneal tumors into T-cell-inflamed tumors in a type-I interferon-dependent manner. Lastly, the STING agonist synergistically cooperated with PD-1 and/or COX2 blockade to further suppress the peritoneal dissemination of colon cancer, resulting in complete eradication of tumor and ascites, and inducing durable antitumor immunity.ConclusionsSTING activation can normalize the peritoneal vascular and immune microenvironment, providing a rationale for a novel combination therapeutic strategy for peritoneal carcinomatosis in colon cancer.

Type I interferon-mediated tumor immunity and its role in immunotherapy

“…Moreover, intraperitoneal administration of ADU-S100 in colon cancer suppressed aberrant angiogenesis and resulted in an inflamed TME in a type I IFN-dependent manner. Consequently, the combination of ADU-S100 and anti-PD-1 antibody further enhanced the antitumor effect [ 139 ]. These preclinical findings supported the clinical trials.…”

Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer

“…STING activation triggers robust type-I IFN secretion from dendritic cells and other stromal cells, stimulates the cross-priming of tumor neoantigens to CD8 + T cells, and finally induces anti-tumor adaptive immunity within the TME [18,81,82]. A previous study showed that intratumoral STING treatment suppressed tumor growth and improved survival in a preclinical model of CRC [20,82,83]. The experimental group showed marked increases in CD8 + cytotoxic T cells and IFN-γ after STING treatment.…”

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

“…Intraperitoneal injection of ADU-S100 into mouse models with peritoneal carcinomatosis of ovarian cancer (ID8) and MC38 colon carcinoma observed inhibition of peritoneal carcinomatosis and malignant ascites progression.ADU-100 effectively reduced abnormal tumor vasculature formation by activating STING-mediated type I IFN and upregulated the number of CD8 + T cells, enhancing the remaining tumor vasculature of pericyte coverage, thereby inhibiting the formation of malignant ascites in the peritoneal cavity. During peritoneal metastasis, type I IFN signaling also inhibited the recruitment of CD206 + M2-like macrophages ( 84 ). Notably, the intratumoral injection of ADU-S100 was shown to be well-tolerated in patients with advanced solid tumors and lymphomas, and no DLT was reported ( 85 ).…”