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Approaches to treat immune hot, altered and cold tumours with combination immunotherapies

Nature Reviews Drug Discovery volume 18, pages 197–218 (2019)Cite this article

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Abstract

Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.

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Fig. 1: Defining ‘hot’, ‘altered’ and ‘cold’ immune tumours — Immunoscore as a new approach for the classification of cancer.
Fig. 2: Overview of more than 2,000 immuno-oncology agents currently tested or in use.
Fig. 3: The tumour–immune classification cycle as a tool to direct anticancer therapy.
Fig. 4: Schematic representation of treatments of immune cold tumours.

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Acknowledgements

The authors thank the following institutions for their financial support: the National Cancer Institute of France (INCa), the Plan Cancer, the Canceropole Ile de France, INSERM, Cancer Research for Personalized Medicine (CARPEM), the Paris Alliance of Cancer Research Institutes (PACRI), H2020 PHC-32-2014 APERIM grant number EEAA15006DDA, MedImmune (grant number RVE15004DSA) and LabEx Immuno-oncology.

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  1. INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Centre de Recherche des Cordeliers, Paris, France

    Jérôme Galon & Daniela Bruni

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  1. Jérôme Galon
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The authors contributed equally to all aspects of the article.

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Correspondence to Jérôme Galon.

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Immunoscore is a registered trademark from INSERM. J.G. is co-founder and chairman of the scientific advisory board of HalioDx. J.G. has patents associated with an ‘in vitro method for the prognosis of progression of a cancer’ (PCT/IB2006/003168 and PCT/EP2013/062405). J.G. established Collaborative Research Agreement (grants) with Perkin-Elmer, IO Biotech, MedImmune, Astra Zeneca, Janssen, Imcheck Therapeutics. J.G. participated to Scientific Advisory Boards of BMS, MedImmune, Astra Zeneca, Novartis, Definiens, Merck Serono, IO Biotech, ImmunID, Nanostring, Illumina, Northwest Biotherapeutics, Actelion, Amgen, Kite Pharma and Merck MSD. J.G. was a consultant for BMS, Roche, GSK, Compugen, Mologen and Sanofi.

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Glossary

TNM system

The tumour-node-metastasis (TNM) staging system is a globally recognized classification of tumours based on their anatomical extent. T refers to the size and extent of the primary tumour, N refers to the involvement of regional lymph nodes and M describes the presence of distant metastases.

Pathologic T (pT) stage

The staging assigned post-surgery to guide treatment stratification, patient selection for clinical trials and prognosis prediction (as opposed to clinical staging that relies on physical exams and imaging tests).

Immunoproteasome

Proteasome isoform constitutively expressed in haematopoietic cells and induced in non-immune cells following exposure to interferon-γ (IFNγ) and other pro-inflammatory cytokines (type I interferons and tumour necrosis factor (TNF)). It is involved in antigen processing and in the expansion, maintenance and differentiation of T cell populations during an immune response.

T cell receptor (TCR) repertoire

The variety of the TCR diversity, as generated by the somatic recombination of the germ line V, D and J gene segments and the deletion and insertion of nucleotides at the V(D)J junctions. Such variety is required to recognize a wide spectrum of antigens.

TCR Vß subfamilies

Human TCR ß locus is on chromosome 7, comprising nine multimember V subfamilies plus additional elements on chromosome 9. The presence of multiple subfamilies is due to evolutionary duplication events.

Tumour-specific antigen

(TSA). Antigen not encoded in the normal genome, expressed exclusively by tumour cells.

Antigenicity

Presence of tumour-associated antigens (TAAs) capable of engaging with T cell receptors or antibodies (B cell receptors), thereby driving adaptive immunity.

Abscopal effect

Phenomenon characterized by the regression of metastases outside the field of radiation after irradiation of one tumour site. Although rarely detected, it is well documented in patients with more immunogenic tumours.

Adjuvanticity

Presence of damage-associated molecular patterns (DAMPs) and stress signals driving the innate immunity.

Genotoxic chemotherapies

Chemical agents that cause DNA damage, such as single-strand and double-strand breaks, loss of excision repair, crosslinking, alkali-labile sites, point mutations and structural and numerical chromosomal aberrations.

Damage-associated molecular patterns

(DAMPs). Intracellular molecules that are hidden from immune recognition under physiological conditions. These molecules are secreted, exposed or released upon cellular stress or tissue injury and recognized by pattern-recognition receptors expressed on innate immune cells.

Tumour-associated antigens

(TAAs). Antigens that are preferentially expressed by tumour cells but they can also be found in normal tissues (except for the TSAs, which are exclusively expressed by tumour cells). They can be broadly categorized into aberrantly expressed self-antigens, mutated self-antigens and TSAs.

(LC3B+) puncta

LC3 is a protein involved in the formation of autophagosomes and autolysosomes. Punctate (as opposed to diffused) LC3 staining indicates autophagy, as determined by fluorescence microscopy.

Differentiation antigens

Antigens derived from proteins that are expressed in a given type of tumour and the corresponding healthy tissue, often in lower amounts.

Neoantigen fitness

The likelihood of a peptide to be immunogenic, as measured by its binding affinity to major histocompatibility complex (MHC) and subsequent recognition by T cells.

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Galon, J., Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 18, 197–218 (2019). https://doi.org/10.1038/s41573-018-0007-y

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