CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer

Au, Katrina; Peterson, Nichole; Truesdell, Peter; Reid-Schachter, Gillian; Khalaj, Kasra; Ren, Runhan; Francis, Julie‐Ann; Graham, Charles H.; Craig, Andrew W.B.; Koti, Madhuri

doi:10.1016/j.ygyno.2017.03.007

Cited by 36 publications

(21 citation statements)

References 44 publications

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“…36 Concurring with this notion, Ad5/3-E2F-D24-hTNFa-IRES-hIL2 treatment of ovarian ex vivo tumor cultures increased the production of IFNg, a cytokine characteristic of heightened TIL activity. Concomitant increase of CXCL10, a chemokine involved in TIL trafficking and OVCA arrest in mice, 37 is concordant with SPECT/CT data from mice and hamsters generated by our group. These studies showed increased infiltration of transferred T cells in murine melanoma and hamster pancreatic tumors injected with adenoviruses coding for TNFa and IL-2.…”

Section: Discussionsupporting

confidence: 88%

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Santos

Heiniö

Cervera-Carrascón³

et al. 2020

J Immunother Cancer

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BackgroundOvarian cancers often contain significant numbers of tumor-infiltrating lymphocytes (TILs) that can be readily harnessed for adoptive T-cell therapy (ACT). However, the immunosuppressive ovarian tumor microenvironment and lack of tumor reactivity in TILs can limit the effectiveness of the therapy. We hypothesized that by using an oncolytic adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) to deliver tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2), we could counteract immunosuppression, and enhance antitumor TIL responses in ovarian cancer (OVCA).MethodsWe established ex vivo tumor cultures freshly derived from patients with advanced OVCA and evaluated the effects of Ad5/3-E2F-D24-hTNFa-IRES-hIL2 or Ad5/3-E2F-D24 (the control virus without TNFa and IL-2) on TILs, cytokine response and tumor viability. Tumor reactivity was assessed by determining interferon gamma (IFNg) response of clinically relevant TILs towards autologous T-cell-depleted ex vivo tumor cultures pretreated with or without the aforementioned oncolytic adenoviruses.ResultsTreatment of ex vivo tumor cultures with Ad5/3-E2F-D24-hTNFa-IRES-hIL2 caused a substantial rise in proinflammatory signals: increased secretion of IFNg, CXCL10, TNFa and IL-2, and concomitant activation of CD4+ and CD8+ TILs. Potent tumor reactivity was seen, as clinically relevant TIL secreted high levels of IFNg in response to autologous T-cell-depleted ovarian ex vivo tumor cultures treated with Ad5/3-E2F-D24-hTNFa-IRES-hIL2. This phenomenon was independent of PD-L1 expression in tumor cells, a factor that determined the variability of IFNg responses seen in different patient samples.ConclusionsOverall, oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 was able to rewire the ovarian tumor microenvironment to accommodate heightened antitumor TIL reactivity. Such effects may improve the clinical effectiveness of ACT with TILs in patients with advanced OVCA.

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Section: Discussionsupporting

confidence: 88%

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Santos

Heiniö

Cervera-Carrascón³

et al. 2020

J Immunother Cancer

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“…It is well established that HGSC tumours exhibit high genomic instability and thus are thought to be immunogenic, contributing to immunologically variant states that can be identified at the time of diagnosis or primary debulking surgery 23 . In line with these characteristics, we and others have previously shown that pre-existing immunologically divergent states also associate with chemotherapy response and overall survival, indicating the significance of IFN induced chemokines and associated ICD in mediating treatment response 10, 24 . It is important to note that a growing body of evidence suggests a co-existence of inflamed and non-inflamed states across multiple regions in one given tumour 25 .…”

Section: Discussionsupporting

confidence: 81%

Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer

Nersesian

Shakfa

Peterson

et al. 2019

Preprint

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Short title: Adding a little STING to chemotherapies in high grade serous ovarian carcinoma: 16 doxorubicin vs carboplatin 17 25overall survival compared to their carboplatin counterparts with further increases following 49 addition of either STING agonist or PD-L1 ICB. However, despite the stronger ICD inducing 50 ability of doxorubicin, overall survival of mice treated with carboplatin + STING agonist + PD-51 L1 ICB was the longest. Findings from our pre-clinical study provide novel insights for 52 rationalized combinations of immune sensitizing agents such as STING pathway activators to 53 improve response of HGSC patients to chemotherapy and ICB in the primary and recurrent 54 settings. 55 56 57

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“…This corresponds well with both findings in human ovarian cancer 27 and several mouse models implicating a role for tumor CXCL10 and CXCR3 expression on T cells, in anti-tumor immunity. 28 , 29 …”

Section: Discussionmentioning

confidence: 99%

Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction

et al. 2017

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Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune suppressive tumor sites. We hypothesized that equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment, could improve tumor homing of T cells. T cells from malignant ascites (n = 13); blood from ovarian cancer (OC) patients (n = 14); and healthy donors (n = 13) were analyzed by flow cytometry. We found that FoxP3+ regulatory T cells accumulation in patients with OC associates with CCR4 expression. We characterized a chemokine profile of ascites chemokines, and expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes (TALs). CCL22, CXCL9, CXCL10 and CXCL12 associated with enrichment of CCR4+, CCR5+, CXCR3+ and CXCR4+ T cells in ascites. Circulating T cells and TALs however did not express CXCR2, identifying CXCR2 as candidate for chemokine receptor transduction. TALs readily expressed IFNγ and TNFα upon stimulation despite the frequency decreasing with in vitro expansion. Lentiviral transduction of TALs (n = 4) with chemokine receptor CXCR2 significantly increased transwell migration of TALs towards rhIL8 and autologous ascites. The majority of expanded and transduced TALs were of a T effector memory subtype. This proof of concept study shows that chemokine receptor engineering with CXCR2 is feasible and improves homing of transduced TALs towards the OC microenvironment.

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CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer

Cited by 36 publications

References 44 publications

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer

Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction

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