Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma
Abstract Background Clinical drawback in checkpoint inhibitors immunotherapy (ICI) of metastatic melanoma (MM) is monitoring clinical benefit. Soluble forms of PD1(sPD1) and PD-L1(sPD-L1) and extracellular vesicles (EVs) expressing PD1 and PD-L1 have recently emerged as predictive biomarkers of resp...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02808-9 |
| _version_ | 1797451032153817088 |
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| author | Simona Serratì Roberta Di Fonte Letizia Porcelli Simona De Summa Ivana De Risi Livia Fucci Eustachio Ruggieri Tommaso Maria Marvulli Sabino Strippoli Rossella Fasano Tania Rafaschieri Gabriella Guida Michele Guida Amalia Azzariti |
| author_facet | Simona Serratì Roberta Di Fonte Letizia Porcelli Simona De Summa Ivana De Risi Livia Fucci Eustachio Ruggieri Tommaso Maria Marvulli Sabino Strippoli Rossella Fasano Tania Rafaschieri Gabriella Guida Michele Guida Amalia Azzariti |
| author_sort | Simona Serratì |
| collection | DOAJ |
| description | Abstract Background Clinical drawback in checkpoint inhibitors immunotherapy (ICI) of metastatic melanoma (MM) is monitoring clinical benefit. Soluble forms of PD1(sPD1) and PD-L1(sPD-L1) and extracellular vesicles (EVs) expressing PD1 and PD-L1 have recently emerged as predictive biomarkers of response. As factors released in the blood, EVs and soluble forms could be relevant in monitoring treatment efficacy and adaptive resistance to ICI. Methods We used pre-therapy plasma samples of 110 MM patients and longitudinal samples of 46 patients. Elisa assay and flow cytometry (FCM) were used to measure sPD-L1 and sPD1 concentrations and the percentage of PD1+ EVs and PD-L1+ EVs, released from tumor and immune cells in patients subsets. Transwell assays were conducted to investigate the impact of EVs of each patient subset on MM cells invasion and interaction between tumor cells and macrophages or dendritic cells. Viability assays were performed to assess EVs effect on MM cells and organoids sensitivity to anti-PD1. FCM was used to investigate immunosuppressive markers in EVs and immune cells. Results The concentrations of sPD1 and sPD-L1 in pre-treatment and longitudinal samples did not correlate with anti-PD1 response, instead only tumor-derived PD1+ EVs decreased in long responders while increased during disease progression in responders. Notably, we observed reduction of T cell derived EVs expressing LAG3+ and PD1+ in long responders and their increase in responders experiencing progression. By investigating the impact of EVs on disease progression, we found that those isolated from non-responders and from patients with progression disease accelerated tumor cells invasiveness and migration towards macrophages, while EVs of long responders reduced the metastatic potential of MM cells and neo-angiogenesis. Additionally, the EVs of non-responders and of progression disease patients subset reduced the sensitivity of MM cells and organoids of responder to anti-PD1 and the recruitment of dendritic cells, while the EVs of progression disease subset skewed macrophages to express higher level of PDL-1. Conclusion Collectively, we suggest that the detection of tumor-derived PD1 + EVs may represent a useful tool for monitoring the response to anti-PD1 and a role for EVs shed by tumor and immune cells in promoting tumor progression and immune dysfunction. Graphical Abstract |
| first_indexed | 2024-03-09T14:49:06Z |
| format | Article |
| id | doaj.art-2b5cecf7a196430a882f23e37244ba42 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-09T14:49:06Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-2b5cecf7a196430a882f23e37244ba422023-11-26T14:34:28ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-09-0142111710.1186/s13046-023-02808-9Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanomaSimona Serratì0Roberta Di Fonte1Letizia Porcelli2Simona De Summa3Ivana De Risi4Livia Fucci5Eustachio Ruggieri6Tommaso Maria Marvulli7Sabino Strippoli8Rossella Fasano9Tania Rafaschieri10Gabriella Guida11Michele Guida12Amalia Azzariti13IRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoDepartment of Basic Medical Sciences Neurosciences and Sense Organs, University of Bari, Piazza G. CesareIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoIRCCS Istituto Tumori Giovanni Paolo II, V.Le O. FlaccoAbstract Background Clinical drawback in checkpoint inhibitors immunotherapy (ICI) of metastatic melanoma (MM) is monitoring clinical benefit. Soluble forms of PD1(sPD1) and PD-L1(sPD-L1) and extracellular vesicles (EVs) expressing PD1 and PD-L1 have recently emerged as predictive biomarkers of response. As factors released in the blood, EVs and soluble forms could be relevant in monitoring treatment efficacy and adaptive resistance to ICI. Methods We used pre-therapy plasma samples of 110 MM patients and longitudinal samples of 46 patients. Elisa assay and flow cytometry (FCM) were used to measure sPD-L1 and sPD1 concentrations and the percentage of PD1+ EVs and PD-L1+ EVs, released from tumor and immune cells in patients subsets. Transwell assays were conducted to investigate the impact of EVs of each patient subset on MM cells invasion and interaction between tumor cells and macrophages or dendritic cells. Viability assays were performed to assess EVs effect on MM cells and organoids sensitivity to anti-PD1. FCM was used to investigate immunosuppressive markers in EVs and immune cells. Results The concentrations of sPD1 and sPD-L1 in pre-treatment and longitudinal samples did not correlate with anti-PD1 response, instead only tumor-derived PD1+ EVs decreased in long responders while increased during disease progression in responders. Notably, we observed reduction of T cell derived EVs expressing LAG3+ and PD1+ in long responders and their increase in responders experiencing progression. By investigating the impact of EVs on disease progression, we found that those isolated from non-responders and from patients with progression disease accelerated tumor cells invasiveness and migration towards macrophages, while EVs of long responders reduced the metastatic potential of MM cells and neo-angiogenesis. Additionally, the EVs of non-responders and of progression disease patients subset reduced the sensitivity of MM cells and organoids of responder to anti-PD1 and the recruitment of dendritic cells, while the EVs of progression disease subset skewed macrophages to express higher level of PDL-1. Conclusion Collectively, we suggest that the detection of tumor-derived PD1 + EVs may represent a useful tool for monitoring the response to anti-PD1 and a role for EVs shed by tumor and immune cells in promoting tumor progression and immune dysfunction. Graphical Abstracthttps://doi.org/10.1186/s13046-023-02808-9Extracellular vesiclesMetastatic melanomaPredictor of anti-PD1 responseAnti-PD1 resistance |
| spellingShingle | Simona Serratì Roberta Di Fonte Letizia Porcelli Simona De Summa Ivana De Risi Livia Fucci Eustachio Ruggieri Tommaso Maria Marvulli Sabino Strippoli Rossella Fasano Tania Rafaschieri Gabriella Guida Michele Guida Amalia Azzariti Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma Journal of Experimental & Clinical Cancer Research Extracellular vesicles Metastatic melanoma Predictor of anti-PD1 response Anti-PD1 resistance |
| title | Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma |
| title_full | Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma |
| title_fullStr | Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma |
| title_full_unstemmed | Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma |
| title_short | Circulating extracellular vesicles are monitoring biomarkers of anti-PD1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma |
| title_sort | circulating extracellular vesicles are monitoring biomarkers of anti pd1 response and enhancer of tumor progression and immunosuppression in metastatic melanoma |
| topic | Extracellular vesicles Metastatic melanoma Predictor of anti-PD1 response Anti-PD1 resistance |
| url | https://doi.org/10.1186/s13046-023-02808-9 |
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