Five latent factors underlie response to immunotherapy

Joseph Usset; Axel Rosendahl Huber; Maria A. Andrianova; Eduard Batlle; Joan Carles; Edwin Cuppen; Elena Elez; Enriqueta Felip; Marina Gómez-Rey; Deborah Lo Giacco; Francisco Martinez-Jimenez; Eva Muñoz-Couselo; Lillian L. Siu; Josep Tabernero; Ana Vivancos; Ferran Muiños; Abel Gonzalez-Perez; Nuria Lopez-Bigas

doi:10.1038/s41588-024-01899-0

Five latent factors underlie response to immunotherapy

Joseph Usset, Axel Rosendahl Huber, Maria A. Andrianova, Eduard Batlle, Joan Carles, Edwin Cuppen, Elena Elez, Enriqueta Felip, Marina Gómez-Rey, Deborah Lo Giacco, Francisco Martinez-Jimenez, Eva Muñoz-Couselo, Lillian L. Siu, Josep Tabernero, Ana Vivancos, Ferran Muiños, Abel Gonzalez-Perez^*, Nuria Lopez-Bigas^*

^*Corresponding author for this work

Group Van Mil, section Molecular Cancer Research

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.

Original language	English
Pages (from-to)	2112-2120
Number of pages	9
Journal	Nature genetics
Volume	56
Issue number	10
Early online date	12 Sept 2024
DOIs	https://doi.org/10.1038/s41588-024-01899-0
Publication status	Published - Oct 2024

Keywords

Humans
Immunotherapy/methods
Tumor Microenvironment/immunology
Biomarkers, Tumor/genetics
Neoplasms/immunology
Immune Checkpoint Inhibitors/therapeutic use
Mutation
Transforming Growth Factor beta/metabolism
Treatment Outcome
Cohort Studies

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Usset, J., Rosendahl Huber, A., Andrianova, M. A., Batlle, E., Carles, J., Cuppen, E., Elez, E., Felip, E., Gómez-Rey, M., Lo Giacco, D., Martinez-Jimenez, F., Muñoz-Couselo, E., Siu, L. L., Tabernero, J., Vivancos, A., Muiños, F., Gonzalez-Perez, A., & Lopez-Bigas, N. (2024). Five latent factors underlie response to immunotherapy. Nature genetics, 56(10), 2112-2120. https://doi.org/10.1038/s41588-024-01899-0

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title = "Five latent factors underlie response to immunotherapy",

abstract = "Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.",

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author = "Joseph Usset and {Rosendahl Huber}, Axel and Andrianova, {Maria A.} and Eduard Batlle and Joan Carles and Edwin Cuppen and Elena Elez and Enriqueta Felip and Marina G{\'o}mez-Rey and {Lo Giacco}, Deborah and Francisco Martinez-Jimenez and Eva Mu{\~n}oz-Couselo and Siu, {Lillian L.} and Josep Tabernero and Ana Vivancos and Ferran Mui{\~n}os and Abel Gonzalez-Perez and Nuria Lopez-Bigas",

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year = "2024",

month = oct,

doi = "10.1038/s41588-024-01899-0",

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Usset, J, Rosendahl Huber, A, Andrianova, MA, Batlle, E, Carles, J, Cuppen, E, Elez, E, Felip, E, Gómez-Rey, M, Lo Giacco, D, Martinez-Jimenez, F, Muñoz-Couselo, E, Siu, LL, Tabernero, J, Vivancos, A, Muiños, F, Gonzalez-Perez, A & Lopez-Bigas, N 2024, 'Five latent factors underlie response to immunotherapy', Nature genetics, vol. 56, no. 10, pp. 2112-2120. https://doi.org/10.1038/s41588-024-01899-0

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AU - Usset, Joseph

AU - Rosendahl Huber, Axel

AU - Andrianova, Maria A.

AU - Batlle, Eduard

AU - Carles, Joan

AU - Cuppen, Edwin

AU - Elez, Elena

AU - Felip, Enriqueta

AU - Gómez-Rey, Marina

AU - Lo Giacco, Deborah

AU - Martinez-Jimenez, Francisco

AU - Muñoz-Couselo, Eva

AU - Siu, Lillian L.

AU - Tabernero, Josep

AU - Vivancos, Ana

AU - Muiños, Ferran

AU - Gonzalez-Perez, Abel

AU - Lopez-Bigas, Nuria

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/10

Y1 - 2024/10

N2 - Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.

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KW - Humans

KW - Immunotherapy/methods

KW - Tumor Microenvironment/immunology

KW - Biomarkers, Tumor/genetics

KW - Neoplasms/immunology

KW - Immune Checkpoint Inhibitors/therapeutic use

KW - Mutation

KW - Transforming Growth Factor beta/metabolism

KW - Treatment Outcome

KW - Cohort Studies

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SN - 1061-4036

VL - 56

SP - 2112

EP - 2120

JO - Nature genetics

JF - Nature genetics

IS - 10

ER -

Five latent factors underlie response to immunotherapy

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