The STING pathway: Therapeutic vulnerabilities in ovarian cancer

Shakfa, Noor; Li, Deyang; Nersesian, Sarah; Wilson-Sanchez, Juliette; Koti, Madhuri

doi:10.1038/s41416-022-01797-4

Cited by 14 publications

(6 citation statements)

References 97 publications

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“…As such, tumors which exhibit inactive immune states resulting from genetic alterations such as PTEN loss may see greater benefit from direct STING pathway and IFN-1 activating therapies (ie, STING agonists following an immunogenic cell death inducing chemotherapy, oncolytic viruses). 45 Indeed, as recently reported, PARP inhibitors and other DDR kinase inhibitors have also been shown to indirectly activate the STING pathway although at a lesser magnitude. 46 47 Our study is not without limitations, particularly, our investigation focuses on the influence of individual and isolated genetic alterations.…”

Section: Discussionmentioning

confidence: 80%

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer

Shakfa

Conseil

et al. 2023

J Immunother Cancer

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BackgroundHigh-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function ofBRCA1andPTENgenes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency.MethodsExpression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53–/–;Pten–/–and ID8-Trp53–/–;Brca1–/–, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy.ResultsPatient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated thatPten-deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared withBrca1-deficient cells; further, tumors from mice injected withPten-deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected withPten-deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived fromPten-deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation.ConclusionsThis study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.

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Section: Discussionmentioning

confidence: 80%

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer

Shakfa

Conseil

et al. 2023

J Immunother Cancer

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“…The majority of patients with PROC was lack of response to immunotherapy attributed to the inadequate immune activation and suppressive TME 3,11,13 . Exogenously Type-I IFN activation presents as an attractive option to enhance antitumor immunity, and cGAS-STING agonists is emerging as a promising avenue 20,24,25 . However, the e cacy of cGAS-STING agonists is constrained by numerous obstacles related to drug delivery and pharmacology.…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary research has indicated that activating the cGAS-STING pathway, along with treatments that induce immunogenic tumor cell death, can boost the sensitivity to ICB treatment and enhance its anti-tumor effects 18,19 . Novel immunomodulatory approaches focusing on interferon activation through cGAS-STING present as a promising avenue 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Manganese primed immunochemotherapy in platinum-resistant/refractory ovarian cancer: a randomized, single-blind, placebo-controlled, phase 2 trial

Han,

Mei,

Zhang

et al. 2024

Preprint

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Platinum-resistant or refractory ovarian cancer (PROC) remains without immunotherapy approval and dismal prognosis, emphasizing the urgent need for novel therapies. This phase 2, single-blind, placebo-controlled, randomized trial evaluated the safety and efficacy of manganese chloride or placebo plus sintilimab, nab-paclitaxel and cisplatin in these patients. 84 patients were randomized to the Mn2+ (n=55) or placebo (n=29) arm. The primary endpoint of objective response rate (ORR) was met at 61.8% in the Mn2+ and 13.8% in placebo group. The secondary endpoints of median PFS (9.8 vs. 3.9 months), OS (21.4 vs. 7.9 months) and DOR (14.9 vs. 1.8 months) were significantly prolonged in the Mn2+ group. No significant differences in AEs and quality of life were document during the treatment period. The serum cytokines and scRNA-seq evidenced the cGAS-STING agonist function of Mn2+. Our study supported Mn2+-priming immunochemotherapy as a promising treatment regimen for PROC patients. ClinicalTrials.gov identifier: NCT03989336.

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“…In contrast, endometrioid tumors were indicated to have a stronger presence of Tregs (FOXP3 and CTLA-4), and tumor PD-L1 and IDO1 levels on par with HGSC. Interestingly, LGSC had high levels of STING, an immune stimulatory target which has been suggested an attractive therapeutic target in OC in general 32 , and has previously been shown to be highly expressed in LGSC in particular 33 . The small set of four clear cell tumors showed an overall weak immune response relative the other histotypes.…”

Section: Discussionmentioning

confidence: 99%

Spatial tumor immune microenvironment phenotypes in ovarian cancer

Gerdtsson,

Mateoiu,

Lokhande

et al. 2024

Preprint

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Immunotherapy has largely failed in ovarian carcinoma (OC), likely due to that the vast tumor heterogeneity and variation in immune response have hampered clinical trial outcomes. Tumor-immune microenvironment (TIME) profiling may aid in stratification of OC tumors for guiding treatment selection. Here, we used Digital Spatial Profiling to characterize regions of spatially distinct TIME phenotypes in OC. Tumors with diffuse immune-infiltration and increased tumor-immune spatial interactions have higher presence of IDO1, PD-L1, PD-1 and Tim-3, while focal immune niches had higher CD163 macrophages and a preliminary worse outcome. Immune exclusion was associated with presence of Tregs and activated fibroblasts. High-grade serous OC showed an overall stronger immune response and presence of multiple targetable checkpoints. Low-grade serous OC was associated with high expression of STING and endometrioid ovarian carcinoma had higher presence of CTLA-4. Mucinous and clear cell OC were dominated by focal immune clusters and immune-excluded regions, with mucinous tumors displaying T-cell rich immune niches, and clear cell tumors an overall low immune activation.

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The STING pathway: Therapeutic vulnerabilities in ovarian cancer

Cited by 14 publications

References 97 publications

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer

Manganese primed immunochemotherapy in platinum-resistant/refractory ovarian cancer: a randomized, single-blind, placebo-controlled, phase 2 trial

Spatial tumor immune microenvironment phenotypes in ovarian cancer

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