Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment

Govindaraj, Chindu; Scalzo-Inguanti, Karen; Madondo, Mutsa; Hallo, Julene; Flanagan, Katie L.; Quinn, Michael; Plebanski, Magdalena

doi:10.1016/j.clim.2013.07.003

Cited by 109 publications

(106 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Expression of TNFRSF1B was observed to correlate with CD3E expression (a marker for T cell infiltration of tumors) [30] for multiple tumor types, including bladder urothelial carcinoma, breast invasive carcinoma, head and neck squamous cell carcinoma, kidney carcinoma, lung squamous cell carcinoma, prostate adenocarcinoma, melanoma, and uterine corpus endometrial carcinoma (Supplementary Figure S7). These data support the hypothesis that tumor-infiltrating Treg and other T cells in multiple tumor types express TNFR2 [31, 32]. …”

Section: Resultssupporting

confidence: 87%

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

Williams¹,

Mistry²,

Guillard³

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.

show abstract

Section: Resultssupporting

confidence: 87%

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

Williams¹,

Mistry²,

Guillard³

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…Others immune factors correlated with bad prognosis are presence of Treg in the tumor [63–66], accumulation of plasmacytoid dendritic cells [67–69] presence of immunosuppressive macrophages expressing B7-H4 [70], low level of circulating lymphocytes (< 1.0 × 109/L) [71]. …”

Section: Immunotherapy In Ovarian Cancermentioning

confidence: 99%

Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge”, Napoli, November 30th 2016

et al. 2017

View full text Add to dashboard Cite

The complex interactions between the immune system and tumors lead the identification of key molecules that govern these interactions: immunotherapeutics were designed to overcome the mechanisms broken by tumors to evade immune destruction. After the substantial advances in melanoma, immunotherapy currently includes many other type of cancers, but the melanoma lesson is essential to progress in other type of cancers, since immunotherapy is potentially improving clinical outcome in various solid and haematologic malignancies. Monotherapy in pre-treated NSCLC is studied and the use of nivolumab, pembrolizumab and atezolizumab as second-line of advanced NSCLC is demonstrated as well as first line monotherapy and combination therapy in metastatic NSCLC studied. Patients with HNSCC have immunotherapeutic promises as well: the FDA recently approved moAbs targeting immune checkpoint receptors. Nivolumab in combination with ipilumumab showed acceptable safety and encouraging antitumor activity in metastatic renal carcinoma. HCCs have significant amounts of genomic heterogeneity and multiple oncogenic pathways can be activated: the best therapeutic targets identification is ongoing. The treatment of advanced/relapsed EOC remain clearly an unmet need: a better understanding of the relevant immuno-oncologic pathways and their corresponding biomarkers are required. UC is an immunotherapy-responsive disease: after atezolizumab, three other PD-L1/PD-L1 inhibitors (nivolumab, durvalumab, and avelumab) were approved for treatment of platinum-refractory metastatic urothelial carcinoma. Anti-PD-1/PD-L1 monotherapy is associated with a modest response rate in metastatic breast cancer; the addition of chemotherapy is associated with higher response rates. Immunotherapy safety profile is advantageous, although, in contrast to conventional chemotherapy: boosting the immune system leads to a unique constellation of inflammatory toxicities known as immune-related Adverse Events (irAEs) that may warrant the discontinuation of therapy and/or the administration of immunosuppressive agents. Research should explore better combination with less side effects, the right duration of treatments, combination or sequencing treatments with target therapies. At present, treatment decision is based on patient’s characteristics.

show abstract

“…Migration assays were performed as previously described (21). In brief, 2.5 Â 10 5 cells in 100 mL of AIM-V media were added to the top chamber, whereas 600 mL of media or cell-free AML bone marrow fluid was added to the lower chamber of 5.0 mmol/L pore size inserts in a 24-well plate (Corning).…”

Section: Flow Cytometry Methods and Analysismentioning

confidence: 99%

“…The role of distinct Treg subsets in AML is currently not known, however, a functionally active Treg subset should have a high bone marrow migratory capacity (16). TNF receptor-2 (TNFR2) expression has recently been demonstrated to identify highly functional Tregs in healthy donors (17,18) and in various diseases such as malaria (19), diabetes (20), and cancer (21). TNFR2…”

Section: Introductionmentioning

confidence: 99%

Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients

Govindaraj

Tan

Walker

et al. 2014

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2þ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2 þ Tregs.Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2 þ Tregs were analyzed subsequently.

show abstract

Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment

Cited by 109 publications

References 98 publications

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge”, Napoli, November 30th 2016

Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients

Contact Info

Product

Resources

About