Oncolytic Viruses Engineered to Enforce Leptin Expression Reprogram Tumor-Infiltrating T Cell Metabolism and Promote Tumor Clearance

Rivadeneira, Dayana B.; DePeaux, Kristin; Wang, Yiyang; Kulkarni, Aditi; Tabib, Tracy; Menk, Ashley V.; Sampath, Padma; Lafyatis, Robert; Ferris, Robert L.; Sarkar, Saumendra N.; Thorne, Stephen H.; Delgoffe, Greg M.

doi:10.1016/j.immuni.2019.07.003

Cited by 103 publications

(100 citation statements)

References 71 publications

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“…However, NMU and GAL were not signi cantly correlated with in ltration of immune cells and TILs. Previous studies suggested that high levels of immune cell in ltration are associated with favorable outcomes [35]. It was similar to our results that increasing levels of B cells, CD8 + T cells, neutrophils, dendritic cells were related to longer survival time in SKCM patients.…”

Section: Moreover Skcm Patients With High Expression Of Ve Chemokinesupporting

confidence: 92%

Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients

Huang

Han

Sheng

et al. 2020

Preprint

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Background：Skin cutaneous melanoma (SKCM) is one of the most malignant and aggressive cancers, causing about 72% of deaths in skin carcinoma. Although extensive study has explored the mechanism of recurrence and metastasis, the tumorigenesis of cutaneous melanoma remains unclear. Exploring the tumorigenesis mechanism may help identify prognostic biomarkers that could serve to guide cancer therapy. Methods：Integrative bioinformatics analyses, including GEO database, TCGA database, DAVID, STRING, Metascape, GEPIA, cBioPortal, TRRUST, TIMER, TISIDB and DGIdb, were performed to unveil the hub genes participating in tumor progression and cancer-associated immunology of SKCM. Furthermore, immunohistochemistry (IHC) staining was performed to validate differential expression levels of hub genes between SKCM tissue and normal tissues from the First Affiliated Hospital of Soochow University cohort. Results: A total of 308 differentially expressed genes (DEGs) and 12 hub genes were found significantly differentially expressed between SKCM and normal skin tissues. Functional annotation indicated that inflammatory response, immune response was closely associated with SKCM tumorigenesis. KEGG pathways in hub genes include IL-10 signaling and chemokine receptors bind chemokine signaling. Five chemokines members (CXCL9, CXCL10, CXCL13, CCL4, CCL5) were associated with better overall survival and pathological stages. IHC results suggested that significantly elevated CXCL9, CXCL10, CXCL13, CCL4 and CCL5 proteins expressed in the SKCM than in the normal tissues. Moreover, our findings suggested that IRF7, RELA, NFKB1, IRF3 and IRF1 are key transcription factors for CCL4, CCL5, CXCL10. In addition, the expressions of CXCL9, CXCL10, CXCL13, CCL4 and CCL5 were positively correlated with infiltration of six immune cells (B-cell, CD8+T cells, CD4+T cells, macrophages, neutrophils, dendritic cells) and 28 types of TILs. Among them, high levels of B cells, CD8+T cells, neutrophils and dendritic cells were significantly related to longer SKCM survival time. Conclusion: In summary, this study mainly identified five chemokine members (CXCL9, CXCL10, CXCL13, CCL4, CCL5) associated with SKCM tumorigenesis, progression, prognosis and immune infiltrations, which might help us evaluate several immune-related targets for cutaneous melanoma therapy.

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Section: Moreover Skcm Patients With High Expression Of Ve Chemokinesupporting

confidence: 92%

Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients

Huang

Han

Sheng

et al. 2020

Preprint

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“…disCussion OVs have been extensively tested for enhancing the efficacy of cancer immunotherapy. [25][26][27][28] Oncolytic vaccinia virus demonstrates very limited infectivity of NK cells 29 30 and can boost the antitumor effects of immune cells instead of impairing their cytotoxic function. 31 32 More importantly, vaccinia virus has been shown not to hinder immune cells in humans in a clinical setting.…”

Section: Synergistic Administration Of Ov and Nk In Vivomentioning

confidence: 99%

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

Sheng

Hou

et al. 2020

J Immunother Cancer

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BackgroundNatural killer (NK) cells have potent antitumor activities. Nevertheless, adoptive transfer therapy of NK cells has gained very limited success in patients with solid tumors as most infused NK cells remain circulating in the peripheral blood instead of entering tumor sites. Chemokines and their receptors play important roles in NK cell distribution. Enhancing chemokine receptors on immune cells to match and be driven to tumor-specific chemokines may improve the therapeutic efficacy of NK cells.MethodsThe CCR5-CCL5 axis is critical in NK cell homing to tumor sites. Thus, we analyzed CCR5 expression on NK cells from patients with cancer and healthy donors. We then upregulated CCR5 and CCL5 with lentiviruses and oncolytic viruses in NK and tumor cells, respectively. Animal experiments were also carried out to test the efficacy of the combination of oncolytic virus with NK cells.ResultsIn NK cells from patients with various solid tumors or healthy subjects, CCR5 was expressed at low levels before and after expansion in vitro. CCR5-engineered NK cells showed enhanced tumor infiltration and antitumor effects, but no complete regressions were noted in the in vivo tumor models. To further improve therapeutic efficacy, we constructed CCL5-expressing oncolytic vaccinia virus. In vitro data demonstrated that vaccinia virus can produce CCL5 in tumor cells while infectivity remained unaffected. Supernatants from tumor cells infected by CCL5-modified vaccinia virus enhanced the directional movement of CCR5-overexpressed NK cells but not green fluorescent protein (GFP)-expressing cells. More importantly, NK cells were resistant to the vaccinia virus and their functions were not affected after being in contact. In vivo assays demonstrated that CCL5-expressing vaccinia virus induced a greater accumulation of NK cells within tumor lesions compared with that of the prototype virus.ConclusionEnhancement of matched chemokines and chemokine receptors is a promising method of increasing NK cell homing and therapeutic effects. Oncolytic vaccinia viruses that express specific chemokines can synergistically augment the efficacies of NK cell-based therapy.

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“…Cells were blocked with α-CD16/32 antibody (BioLegend; Cat#101319, Clone 93) in FACS buffer for 10 min and then stained with PerCp/ Cy5.5-conjugated CD45 antibody (BioLegend; Cat# 103131, Clone: 30-F11), VioGreen-conjugated CD8 antibody (Miltenyi Biotec; Cat# 130-109-252, Clone: REA601), FITC-conjugated CD4 antibody (BioLegend; Cat#130308, Clone: H129. 19) and PE-conjugated PD-L1 antibody (BD Biosciences; Cat#558091, Clone: MIH5) for 30 min at 4°C in dark. In a separate staining panel, cells were stained for surface antigens and permeabilized using BD fix/perm kit (BD Biosciences; Cat#554714).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…15 However, recent studies have shown that the success of OVs is as much as, or more, dependent on their immune-modulating capability as it is on their ability to directly kill cancer cells. [15][16][17][18][19] OVs could modulate the immunological landscape in TME through a variety of different mechanisms. 20 For example, OVs have been shown to induce immunogenic cell death which plays an important role in the induction of adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic poxvirus CF33-hNIS-ΔF14.5 favorably modulates tumor immune microenvironment and works synergistically with anti-PD-L1 antibody in a triple-negative breast cancer model

et al. 2020

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Triple-negative breast cancer is the most aggressive subtype of breast cancer and is difficult to treat. Breast cancer is considered to be poorly immunogenic and hence is less responsive to immunotherapies. We tested whether the oncolytic poxvirus CF33-hNIS-ΔF14.5 could modulate tumor immune microenvironment and make the tumors responsive to the immune checkpoint inhibitor anti-PD-L1. We found that virus infection causes the upregulation of PD-L1 levels on triple-negative breast cancer cells in vitro as well as in vivo in mice. In a mouse model of orthotopic triple-negative breast cancer, the virus was found to increase tumor infiltration by CD8+ T cells. Likewise, in mice treated with CF33-hNIS-ΔF14.5 high levels of proinflammatory cytokines IFNγ and IL-6 were found in the tumors but not in the serum. The levels of immune modulation were even higher in mice that were treated with a combination of the virus and anti-PD-L1 antibody. While CF33-hNIS-ΔF14.5 and anti-PD-L1 antibody failed to exert significant anti-tumor effect as a single agent, a combination of the two agents resulted in significant antitumor effect with 50% mice experiencing complete tumor regression when both agents were injected intra-tumorally. Furthermore, the 'cured' mice did not develop tumor after re-challenge with the same cancer cells suggesting that they developed immunity against those cancer cells. Taken together, our study shows that CF33-hNIS-ΔF14.5 favorably modulates tumor immune microenvironment in triplenegative breast cancer model making them responsive to the immune checkpoint inhibitor anti-PD-L1, and hence warrants further studies to determine the clinical applicability of this combination therapy.

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Oncolytic Viruses Engineered to Enforce Leptin Expression Reprogram Tumor-Infiltrating T Cell Metabolism and Promote Tumor Clearance

Cited by 103 publications

References 71 publications

Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients

Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

Oncolytic poxvirus CF33-hNIS-ΔF14.5 favorably modulates tumor immune microenvironment and works synergistically with anti-PD-L1 antibody in a triple-negative breast cancer model

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