Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma

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Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma. / Frias, Alex; Di Leo, Luca; Antoranz, Asier; Nazerai, Loulieta; Carretta, Marco; Bodemeyer, Valérie; Pagliuca, Chiara; Dahl, Christina; Claps, Giuseppina; Mandelli, Giulio Eugenio; Andhari, Madhavi Dipak; Pacheco, Maria Pires; Sauter, Thomas; Robert, Caroline; Guldberg, Per; Madsen, Daniel Hargbøl; Cecconi, Francesco; Bosisio, Francesca Maria; De Zio, Daniela.

In: Journal for ImmunoTherapy of Cancer, Vol. 11, No. 3, e006389, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Frias, A, Di Leo, L, Antoranz, A, Nazerai, L, Carretta, M, Bodemeyer, V, Pagliuca, C, Dahl, C, Claps, G, Mandelli, GE, Andhari, MD, Pacheco, MP, Sauter, T, Robert, C, Guldberg, P, Madsen, DH, Cecconi, F, Bosisio, FM & De Zio, D 2023, 'Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma', Journal for ImmunoTherapy of Cancer, vol. 11, no. 3, e006389. https://doi.org/10.1136/jitc-2022-006389

APA

Frias, A., Di Leo, L., Antoranz, A., Nazerai, L., Carretta, M., Bodemeyer, V., Pagliuca, C., Dahl, C., Claps, G., Mandelli, G. E., Andhari, M. D., Pacheco, M. P., Sauter, T., Robert, C., Guldberg, P., Madsen, D. H., Cecconi, F., Bosisio, F. M., & De Zio, D. (2023). Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma. Journal for ImmunoTherapy of Cancer, 11(3), [e006389]. https://doi.org/10.1136/jitc-2022-006389

Vancouver

Frias A, Di Leo L, Antoranz A, Nazerai L, Carretta M, Bodemeyer V et al. Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma. Journal for ImmunoTherapy of Cancer. 2023;11(3). e006389. https://doi.org/10.1136/jitc-2022-006389

Author

Frias, Alex ; Di Leo, Luca ; Antoranz, Asier ; Nazerai, Loulieta ; Carretta, Marco ; Bodemeyer, Valérie ; Pagliuca, Chiara ; Dahl, Christina ; Claps, Giuseppina ; Mandelli, Giulio Eugenio ; Andhari, Madhavi Dipak ; Pacheco, Maria Pires ; Sauter, Thomas ; Robert, Caroline ; Guldberg, Per ; Madsen, Daniel Hargbøl ; Cecconi, Francesco ; Bosisio, Francesca Maria ; De Zio, Daniela. / Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma. In: Journal for ImmunoTherapy of Cancer. 2023 ; Vol. 11, No. 3.

Bibtex

@article{a60e6f75f9364d99b9334e89eb7ea6b0,
title = "Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma",
abstract = "BACKGROUND: Loss of Ambra1 (autophagy and beclin 1 regulator 1), a multifunctional scaffold protein, promotes the formation of nevi and contributes to several phases of melanoma development. The suppressive functions of Ambra1 in melanoma are mediated by negative regulation of cell proliferation and invasion; however, evidence suggests that loss of Ambra1 may also affect the melanoma microenvironment. Here, we investigate the possible impact of Ambra1 on antitumor immunity and response to immunotherapy.METHODS: This study was performed using an Ambra1-depleted BrafV600E /Pten-/ - genetically engineered mouse (GEM) model of melanoma, as well as GEM-derived allografts of BrafV600E /Pten-/ - and BrafV600E /Pten-/ -/Cdkn2a-/ - tumors with Ambra1 knockdown. The effects of Ambra1 loss on the tumor immune microenvironment (TIME) were analyzed using NanoString technology, multiplex immunohistochemistry, and flow cytometry. Transcriptome and CIBERSORT digital cytometry analyses of murine melanoma samples and human melanoma patients (The Cancer Genome Atlas) were applied to determine the immune cell populations in null or low-expressing AMBRA1 melanoma. The contribution of Ambra1 on T-cell migration was evaluated using a cytokine array and flow cytometry. Tumor growth kinetics and overall survival analysis in BrafV600E /Pten-/ -/Cdkn2a-/ - mice with Ambra1 knockdown were evaluated prior to and after administration of a programmed cell death protein-1 (PD-1) inhibitor.RESULTS: Loss of Ambra1 was associated with altered expression of a wide range of cytokines and chemokines as well as decreased infiltration of tumors by regulatory T cells, a subpopulation of T cells with potent immune-suppressive properties. These changes in TIME composition were associated with the autophagic function of Ambra1. In the BrafV600E /Pten-/ -/Cdkn2a-/ - model inherently resistant to immune checkpoint blockade, knockdown of Ambra1 led to accelerated tumor growth and reduced overall survival, but at the same time conferred sensitivity to anti-PD-1 treatment.CONCLUSIONS: This study shows that loss of Ambra1 affects the TIME and the antitumor immune response in melanoma, highlighting new functions of Ambra1 in the regulation of melanoma biology.",
keywords = "Humans, Animals, Mice, Proto-Oncogene Proteins B-raf, Melanoma, Autophagy, Cell Movement, Cell Proliferation, Cytokines, Tumor Microenvironment, Adaptor Proteins, Signal Transducing",
author = "Alex Frias and {Di Leo}, Luca and Asier Antoranz and Loulieta Nazerai and Marco Carretta and Val{\'e}rie Bodemeyer and Chiara Pagliuca and Christina Dahl and Giuseppina Claps and Mandelli, {Giulio Eugenio} and Andhari, {Madhavi Dipak} and Pacheco, {Maria Pires} and Thomas Sauter and Caroline Robert and Per Guldberg and Madsen, {Daniel Hargb{\o}l} and Francesco Cecconi and Bosisio, {Francesca Maria} and {De Zio}, Daniela",
note = "{\textcopyright} Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2023",
doi = "10.1136/jitc-2022-006389",
language = "English",
volume = "11",
journal = "Journal for ImmunoTherapy of Cancer",
issn = "2051-1426",
publisher = "BioMed Central Ltd.",
number = "3",

}

RIS

TY - JOUR

T1 - Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma

AU - Frias, Alex

AU - Di Leo, Luca

AU - Antoranz, Asier

AU - Nazerai, Loulieta

AU - Carretta, Marco

AU - Bodemeyer, Valérie

AU - Pagliuca, Chiara

AU - Dahl, Christina

AU - Claps, Giuseppina

AU - Mandelli, Giulio Eugenio

AU - Andhari, Madhavi Dipak

AU - Pacheco, Maria Pires

AU - Sauter, Thomas

AU - Robert, Caroline

AU - Guldberg, Per

AU - Madsen, Daniel Hargbøl

AU - Cecconi, Francesco

AU - Bosisio, Francesca Maria

AU - De Zio, Daniela

N1 - © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023

Y1 - 2023

N2 - BACKGROUND: Loss of Ambra1 (autophagy and beclin 1 regulator 1), a multifunctional scaffold protein, promotes the formation of nevi and contributes to several phases of melanoma development. The suppressive functions of Ambra1 in melanoma are mediated by negative regulation of cell proliferation and invasion; however, evidence suggests that loss of Ambra1 may also affect the melanoma microenvironment. Here, we investigate the possible impact of Ambra1 on antitumor immunity and response to immunotherapy.METHODS: This study was performed using an Ambra1-depleted BrafV600E /Pten-/ - genetically engineered mouse (GEM) model of melanoma, as well as GEM-derived allografts of BrafV600E /Pten-/ - and BrafV600E /Pten-/ -/Cdkn2a-/ - tumors with Ambra1 knockdown. The effects of Ambra1 loss on the tumor immune microenvironment (TIME) were analyzed using NanoString technology, multiplex immunohistochemistry, and flow cytometry. Transcriptome and CIBERSORT digital cytometry analyses of murine melanoma samples and human melanoma patients (The Cancer Genome Atlas) were applied to determine the immune cell populations in null or low-expressing AMBRA1 melanoma. The contribution of Ambra1 on T-cell migration was evaluated using a cytokine array and flow cytometry. Tumor growth kinetics and overall survival analysis in BrafV600E /Pten-/ -/Cdkn2a-/ - mice with Ambra1 knockdown were evaluated prior to and after administration of a programmed cell death protein-1 (PD-1) inhibitor.RESULTS: Loss of Ambra1 was associated with altered expression of a wide range of cytokines and chemokines as well as decreased infiltration of tumors by regulatory T cells, a subpopulation of T cells with potent immune-suppressive properties. These changes in TIME composition were associated with the autophagic function of Ambra1. In the BrafV600E /Pten-/ -/Cdkn2a-/ - model inherently resistant to immune checkpoint blockade, knockdown of Ambra1 led to accelerated tumor growth and reduced overall survival, but at the same time conferred sensitivity to anti-PD-1 treatment.CONCLUSIONS: This study shows that loss of Ambra1 affects the TIME and the antitumor immune response in melanoma, highlighting new functions of Ambra1 in the regulation of melanoma biology.

AB - BACKGROUND: Loss of Ambra1 (autophagy and beclin 1 regulator 1), a multifunctional scaffold protein, promotes the formation of nevi and contributes to several phases of melanoma development. The suppressive functions of Ambra1 in melanoma are mediated by negative regulation of cell proliferation and invasion; however, evidence suggests that loss of Ambra1 may also affect the melanoma microenvironment. Here, we investigate the possible impact of Ambra1 on antitumor immunity and response to immunotherapy.METHODS: This study was performed using an Ambra1-depleted BrafV600E /Pten-/ - genetically engineered mouse (GEM) model of melanoma, as well as GEM-derived allografts of BrafV600E /Pten-/ - and BrafV600E /Pten-/ -/Cdkn2a-/ - tumors with Ambra1 knockdown. The effects of Ambra1 loss on the tumor immune microenvironment (TIME) were analyzed using NanoString technology, multiplex immunohistochemistry, and flow cytometry. Transcriptome and CIBERSORT digital cytometry analyses of murine melanoma samples and human melanoma patients (The Cancer Genome Atlas) were applied to determine the immune cell populations in null or low-expressing AMBRA1 melanoma. The contribution of Ambra1 on T-cell migration was evaluated using a cytokine array and flow cytometry. Tumor growth kinetics and overall survival analysis in BrafV600E /Pten-/ -/Cdkn2a-/ - mice with Ambra1 knockdown were evaluated prior to and after administration of a programmed cell death protein-1 (PD-1) inhibitor.RESULTS: Loss of Ambra1 was associated with altered expression of a wide range of cytokines and chemokines as well as decreased infiltration of tumors by regulatory T cells, a subpopulation of T cells with potent immune-suppressive properties. These changes in TIME composition were associated with the autophagic function of Ambra1. In the BrafV600E /Pten-/ -/Cdkn2a-/ - model inherently resistant to immune checkpoint blockade, knockdown of Ambra1 led to accelerated tumor growth and reduced overall survival, but at the same time conferred sensitivity to anti-PD-1 treatment.CONCLUSIONS: This study shows that loss of Ambra1 affects the TIME and the antitumor immune response in melanoma, highlighting new functions of Ambra1 in the regulation of melanoma biology.

KW - Humans

KW - Animals

KW - Mice

KW - Proto-Oncogene Proteins B-raf

KW - Melanoma

KW - Autophagy

KW - Cell Movement

KW - Cell Proliferation

KW - Cytokines

KW - Tumor Microenvironment

KW - Adaptor Proteins, Signal Transducing

U2 - 10.1136/jitc-2022-006389

DO - 10.1136/jitc-2022-006389

M3 - Journal article

C2 - 36868570

VL - 11

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

SN - 2051-1426

IS - 3

M1 - e006389

ER -

ID: 338891232