Tumour-reactive T cell subsets in the microenvironment of ovarian cancer

Westergaard, Marie Christine Wulff; Andersen, Rikke; Chong, Chloé; Kjeldsen, Julie Westerlin; Pedersen, Magnus; Friese, Christina; Hasselager, Thomas; Lajer, Henrik; Coukos, George; Bassani-Sternberg, Michal; Donia, Marco; Svane, Inge Marie

doi:10.1038/s41416-019-0384-y

Cited by 46 publications

(53 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study reported that TIL culture resulted in grafts with a high CD4-to-CD8 cell ratio. 47 In contrast, we and others have frequently seen the inverse situation, perhaps reflecting variations in the TIL production protocols, 44 such as the concentration of IL-2 used. 47 In ACT with TILs, IL-2 is used for the in vivo maintenance of the TIL graft activity.…”

Section: Discussionmentioning

confidence: 85%

“…47 In contrast, we and others have frequently seen the inverse situation, perhaps reflecting variations in the TIL production protocols, 44 such as the concentration of IL-2 used. 47 In ACT with TILs, IL-2 is used for the in vivo maintenance of the TIL graft activity. 4 Thus, production of IL-2 by Ad5/3-E2F-D24-hTNFa-IRES-hIL2 may explain the increase of TIL-derived IFNg seen (figure 4).…”

Section: Discussionmentioning

confidence: 85%

See 1 more Smart Citation

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

Santos

Heiniö

Cervera-Carrascón³

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 85%

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

Santos

Heiniö

Cervera-Carrascón³

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…In a pilot study, ACT with TILs of patients with metastatic ovarian cancer resulted in a slight decrease of tumour size (maximally 23%) in five of six patients, but the effect was transient [94]. One of the reasons of a relatively modest therapeutic effect might be a low frequency (3%) of tumour-reactive T cells in ex vivo expanded TIL cultures [95]. Functional characterisation of expanded TILs from renal cell carcinoma and gastrointestinal cancer (GI) also revealed lower frequency of tumour-specific T cells compared to melanoma [96,97].…”

Section: Selected Ex Vivo Expanded Tumour-reactive Tils Vs Unselectementioning

confidence: 95%

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Chruściel

Urban-Wójciuk

Arcimowicz

et al. 2020

Cancers

View full text Add to dashboard Cite

In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies.

show abstract

“…ovarian cancer with ACT completed at our center have shown that ACT in metastatic ovarian cancer is feasible, but clinical responses were transient 25,26 . A phase I/II study combining ACT with checkpoint inhibitors has just been finalized (Kverneland et al, manuscript in preparation).…”

mentioning

confidence: 99%

CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer

Friese

Harbst

Borch

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8 + T-cell output and TIL tumor reactivity. To exploit this, we used a CTLA-4-blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8 + TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase. Thus, targeting CTLA-4 within the intact tumor microenvironment of tumor fragments enriches tumorreactive TILs and may improve clinical outcome of TIL-based ACT in ovarian cancer.Ovarian cancer is the eighth most common cause of cancer death in women worldwide 1 . Ovarian cancer is often diagnosed at an advanced stage (e.g. International Federation of Gynecology and Obstetrics (FIGO) stage III or IV) 2,3 and often characterized by a high tumor burden at diagnosis 2 . The primary treatments consist of platinum-based chemotherapy and surgery 3 , but the majority of patients with ovarian cancer relapse after the initial treatment 3 . The prognosis of advanced ovarian cancer is very poor, with a 5-year survival of 39% and 17% in stage III and IV, respectively 4 . Thus, more efficient treatment modalities are highly warranted.Checkpoint inhibitors have demonstrated clinical benefit in a small proportion of patients with ovarian cancer. Responses to checkpoint inhibitors have been reported consistently at rates below 15% 5-9 .Several studies have previously demonstrated a positive prognostic value of tumor-infiltrating lymphocytes (TIL) in ovarian cancer. The presence of intraepithelial CD8 + cytotoxic TILs is associated with improved survival 10-12 . On the other hand, infiltration with regulatory T cells (Tregs), which can inhibit cytotoxic T cells, is associated with a poor prognosis 13 . Additionally, Sato et al. demonstrated that a high CD8 + /Tregs ratio is associated with improved survival 12 .Adoptive T-cell therapy (ACT) based on autologous TILs takes advantage of tumor-reactive T cells naturally present in the tumor lesions 14 and has shown overall response rates of around 50% with durable complete responses in 15-20% of the patients in metastatic melanoma [15][16][17][18][19][20] . In addition, clinical responses in other epithelial cancers with...

show abstract

Tumour-reactive T cell subsets in the microenvironment of ovarian cancer

Cited by 46 publications

References 42 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

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer

Contact Info

Product

Resources

About