Human mesothelioma induces defects in dendritic cell numbers and antigen-processing function which predict survival outcomes

Cornwall, Scott; Wikström, Matthew E.; Musk, Arthur W.; Alvarez, John; Nowak, Anna K.; Nelson, Delia J.

doi:10.1080/2162402x.2015.1082028

Cited by 19 publications

(16 citation statements)

References 58 publications

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“…1 8 Compared with healthy individuals, in MPM patients circulating dendritic cells (DCs) are reduced in numbers and antigen-processing capacity, which is thought to contribute to the low numbers of TILs. 9 Previously, we developed a DC-mediated immunotherapy for MPM with the aim to increase the number of TILs and tumor-directed T cells. 10 Patients received multiple vaccinations with autologous DCs loaded with autologous tumor cell lysate.…”

Section: Introductionmentioning

confidence: 99%

T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

Vroman

Balzaretti

Belderbos

et al. 2020

J Immunother Cancer

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BackgroundMalignant pleural mesothelioma (MPM) is a highly lethal malignancy in need for new treatment options. Although immunotherapies have been shown to boost a tumor-specific immune response, not all patients respond and prognostic biomarkers are scarce. In this study, we determined the peripheral blood T cell receptor β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy.Materials and methodsWe separately profiled PD1+and PD1−CD4+and CD8+T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient.ResultsStrikingly, limited TCRβ repertoire diversity and high average clone sizes in total CD3+T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCRβ repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCRβ clones present in the total CD3+T cell fractions were classified into five categories, based on therapy-associated frequency changes: expanding, decreasing, stable, newly appearing and disappearing clones. Subsequently, the presence of these five groups of clones was analyzed in the individual sorted T cell fractions. DC-therapy primarily induced TCRβ repertoire changes in the PD1+CD4+and PD1+CD8+T cell fractions. In particular, in the PD1+CD8+T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1−to a PD1+phenotype was significantly more frequent in CD8+T cells than in CD4+T cells. Hereby, the number of expanding PD1+CD8+T cell clones—and not expanding PD1+CD4+T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume.ConclusionWe conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCRβ repertoire of total CD3+T cells and on therapy-induced changes, in particular expanding PD1+CD8+T cell clones. Therefore, TCRβ repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy.Trial registration numberNCT02395679.

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Section: Introductionmentioning

confidence: 99%

T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

Vroman

Balzaretti

Belderbos

et al. 2020

J Immunother Cancer

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“…Dendritic cell (DC)-based immunotherapy is a potent cellbased immunotherapeutic approach (10,11), which aims to boost the immune system of cancer patients by enhancing tumor antigen presentation and subsequent activation of tumor-specific (cytotoxic) T cells. DCs are reduced in number in the peripheral blood of mesothelioma patients, and are less functional in terms of activation and antigen presentation compared with healthy controls (12). Therefore, ex vivo DC activation and maturation might improve their immune function and direct them to present tumor-associated antigens (TAA).…”

Section: Introductionmentioning

confidence: 99%

Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human

Aerts

Goeje

Cornelissen

et al. 2018

Clinical Cancer Research

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Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans. First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte-derived DCs pulsed with tumor lysate from five mesothelioma cell lines. In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1-20.3] and median OS not reached (median follow-up = 22.8 months). DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. .

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“…Boosting DC response may be of particular interest in mesothelioma patients. Cornwall and colleagues documented a defect in DC numbers and maturation in mesothelioma patients; the larger the reduction in circulating DC, the shorter the survival of mesothelioma patients [14]. In particular, these authors identified a reduced ability to process antigens and a reduced expression of costimulatory and MHC molecules relative to the healthy controls.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, these authors identified a reduced ability to process antigens and a reduced expression of costimulatory and MHC molecules relative to the healthy controls. Moreover, such dysfunction was found to be irreversible, as documented by the incapacity of monocyte-derived DC from MM patients to process antigens to the same levels as their healthy counterparts [14]. The use of exogenously primed DC may further counteract the known immunosuppressive environment of mesothelioma [12].…”

Section: Discussionmentioning

confidence: 99%

“…Third, MMs are usually associated with an immunosuppressive microenvironment including the presence of interleukin-10 (IL-10), VEGF, prostaglandin E2 (PGE2) and transforming growth factor-beta (TGF-β) [12,13]. Fourth, MM patients were reported to present a decreased number of circulating DCs (relative to healthy age and gender-matched controls) associated with a reduced ability to process antigens and a reduced expression of costimulatory and major histocompatibility complex (MHC) molecules [14].…”

Section: Introductionmentioning

confidence: 99%

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Photodynamic Therapy-Based Dendritic Cell Vaccination Suited to Treat Peritoneal Mesothelioma

Trempolec

Doix

Degavre

et al. 2020

Cancers

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The potential of dendritic cell (DC)-based immunotherapy to treat cancer is, nowadays, well documented. Still, the clinical success of immune checkpoint inhibitors has dampened the interest in anticancer DC vaccination. For highly life-threatening tumors that are regarded as nonimmunogenic, such as mesothelioma, however, T helper 1 immunity-biased DC-based immunotherapy could still represent an attractive strategy. In this study, we took advantage of photodynamic therapy (PDT) to induce immunogenic cell death to generate mesothelioma cell lysates for DC priming and evaluated such a vaccine to treat peritoneal mesothelioma. We found that the white light in vitro activation of the photosensitizer OR141 led to mesothelioma cell death, together with the release of bona fide danger signals that promote DC maturation. The administration of a PDT-based DC vaccine to mice bearing peritoneal mesothelioma led to highly significant survival when compared with sham or control animals treated with anti-CTLA4 antibodies. This was further supported by a strong CD8+ and CD4+ T cell response, characterized by an increased proliferation, cytotoxic activities and the expression of activation markers, including interferon gamma (IFNγ). Moreover, the PDT-based DC vaccine led to a significant increase in IFNγ+ T cells infiltered within mesothelioma, as determined by flow cytometry and immunohistochemistry. Finally, in vivo tracking of intraperitoneally administered DCs led us to document rapid chemotaxis towards tumor-occupied lymphatics (vs. lipopolysaccharide (LPS)-treated DC). DCs pulsed with PDT-killed mesothelioma cells also exhibited a significant increase in CCR7 receptors, together with an intrinsic capacity to migrate towards the lymph nodes. Altogether, these results indicate that PDT-based DC vaccination is particularly suited to induce a potent immune response against peritoneal mesothelioma.

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Human mesothelioma induces defects in dendritic cell numbers and antigen-processing function which predict survival outcomes

Cited by 19 publications

References 58 publications

T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human

Photodynamic Therapy-Based Dendritic Cell Vaccination Suited to Treat Peritoneal Mesothelioma

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