Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients
Abstract Background We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who r...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0633-x |
| _version_ | 1828383720283832320 |
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| author | Silvia C. Formenti Rachael E. Hawtin Neha Dixit Erik Evensen Percy Lee Judith D. Goldberg Xiaochun Li Claire Vanpouille-Box Dörthe Schaue William H. McBride Sandra Demaria |
| author_facet | Silvia C. Formenti Rachael E. Hawtin Neha Dixit Erik Evensen Percy Lee Judith D. Goldberg Xiaochun Li Claire Vanpouille-Box Dörthe Schaue William H. McBride Sandra Demaria |
| author_sort | Silvia C. Formenti |
| collection | DOAJ |
| description | Abstract Background We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP). Methods The original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression. Results At baseline, a significantly higher level of expression (p < 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1+ cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1+ T cells and not in PD-1- T cells or in PD-1+ T cells from HD. Conclusions Functional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy. Trial registration NCT01401062. |
| first_indexed | 2024-12-10T04:54:09Z |
| format | Article |
| id | doaj.art-e6b2d5724ebd4e2aa865a8b4b39e445d |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-10T04:54:09Z |
| publishDate | 2019-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-e6b2d5724ebd4e2aa865a8b4b39e445d2022-12-22T02:01:33ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-07-01711810.1186/s40425-019-0633-xBaseline T cell dysfunction by single cell network profiling in metastatic breast cancer patientsSilvia C. Formenti0Rachael E. Hawtin1Neha Dixit2Erik Evensen3Percy Lee4Judith D. Goldberg5Xiaochun Li6Claire Vanpouille-Box7Dörthe Schaue8William H. McBride9Sandra Demaria10Department of Radiation Oncology, Weill Cornell MedicineNodalityNodalityNodalityDepartment of Radiation oncology, UCLA David Geffen School of MedicineDepartment of Population Health and Environmental Medicine, New York University School of MedicineDepartment of Population Health and Environmental Medicine, New York University School of MedicineDepartment of Radiation Oncology, Weill Cornell MedicineDepartment of Radiation oncology, UCLA David Geffen School of MedicineDepartment of Radiation oncology, UCLA David Geffen School of MedicineDepartment of Radiation Oncology, Weill Cornell MedicineAbstract Background We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP). Methods The original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression. Results At baseline, a significantly higher level of expression (p < 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1+ cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1+ T cells and not in PD-1- T cells or in PD-1+ T cells from HD. Conclusions Functional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy. Trial registration NCT01401062.http://link.springer.com/article/10.1186/s40425-019-0633-xImmunotherapyRadiotherapyT cell receptor (TCR) signalingProgrammed Death-1 (PD-1) |
| spellingShingle | Silvia C. Formenti Rachael E. Hawtin Neha Dixit Erik Evensen Percy Lee Judith D. Goldberg Xiaochun Li Claire Vanpouille-Box Dörthe Schaue William H. McBride Sandra Demaria Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients Journal for ImmunoTherapy of Cancer Immunotherapy Radiotherapy T cell receptor (TCR) signaling Programmed Death-1 (PD-1) |
| title | Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients |
| title_full | Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients |
| title_fullStr | Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients |
| title_full_unstemmed | Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients |
| title_short | Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients |
| title_sort | baseline t cell dysfunction by single cell network profiling in metastatic breast cancer patients |
| topic | Immunotherapy Radiotherapy T cell receptor (TCR) signaling Programmed Death-1 (PD-1) |
| url | http://link.springer.com/article/10.1186/s40425-019-0633-x |
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