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Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination

Eleonore De Guillebon

Corresponding Author

E-mail address: eleonore.deguillebon@curie.fr

Department of medical Oncology, Institut Curie, Paris, France

Correspondence to: Eleonore de Guillebon E‐mail:

eleonore.deguillebon@curie.fr

or Eric Tartour E‐mail:

eric.tartour@aphp.fr

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Antoine Dardenne

Department of Gastro‐enterology and Gastro‐intestinal Oncology, Hopital européen Georges Pompidou, APHP, Paris, France

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Antonin Saldmann

Université de Paris, PARCC, INSERM, Paris, France

Department of Immunology, AP‐HP, Hopital Européen Georges Pompidou, APHP, Paris, France

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Sylvie Séguier

Université de Paris, PARCC, INSERM, Paris, France

Hôpital Louis Mourier, Faculté de Chirurgie dentaire, Montrouge, France

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Thi Tran

Université de Paris, PARCC, INSERM, Paris, France

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Lea Paolini

Université de Paris, PARCC, INSERM, Paris, France

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Celeste Lebbe

Department of Dermatology, Saint‐Louis University Hospital, Paris, France

Université de Paris, INSERM U976, Paris, France

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Eric Tartour

Corresponding Author

E-mail address: eric.tartour@aphp.fr

Université de Paris, PARCC, INSERM, Paris, France

Department of Immunology, AP‐HP, Hopital Européen Georges Pompidou, APHP, Paris, France

Equipe Labellisée Ligue contre le Cancer

Correspondence to: Eleonore de Guillebon E‐mail:

eleonore.deguillebon@curie.fr

or Eric Tartour E‐mail:

eric.tartour@aphp.fr

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First published: 30 January 2020
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ijc.32889.

Abstract

Immunotherapy has revolutionized the management of cancers. At the end of 2018, 1,716 clinical trials assessed regimen that combine Program Death‐1 (PD‐1)/ Program Death Ligand‐1 (PD‐L1) blockers with other cancer therapies (tyrosine kinase inhibitor, chemotherapy, radiotherapy). There is a contrast between this clinical dynamics and the difficulty of identifying biomarkers to better select patients that could benefit from immunotherapy. In this context, different tumor classifications have been proposed to try to better stratify patients. They rely on the characteristics of the tumor microenvironment and led first to divide them into hot and cold tumors. In this review we aim to demonstrate the limitations of this classification focusing on the differential significance of subpopulations of intratumor CD8 + T cells. We also underline novel mechanisms of resistance to anti PD‐1 / PD‐L1 blockade, focusing on myeloid cells, hypoxia and tumor immunoediting under treatment. Understanding the mechanisms of resistance to immune‐checkpoint inhibitor is indeed a powerful research driver that allows further identification of novel biomarkers, drug development and bring a rational to innovative therapeutic combinations.

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