Combination Immunotherapies for Immune Hot, Altered and Cold Tumours

Understanding underlining mechanisms is crucial to boost a weak antitumour immunity

In an article recently published in the Nature Reviews Drug Discovery, Jérôme Galon of the INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Centre de Recherche des Cordeliers, Paris, France focuses on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and describe approaches to treat such tumours. 

The colder the tumour is, the more approaches are needed. Interestingly, all proposed therapeutic designs ultimately involve combinations with immunotherapies to achieve maximal efficiency.

Effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In the upcoming era of combination immunotherapy, it is critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity.

An observation that the type, density and location of immune cells within the tumour site could predict survival in colorectal cancer more accurately than the classical TNM system

led to the development and implementation of the Immunoscore. It is a robust, consensus, standardised scoring system based on the quantification of CD3 and CD8 lymphocyte populations at the tumour centre and the invasive margin. The Immunoscore ranges from Immunoscore 0 to 4. By classifying cancers according to their immune infiltration, the system proposed for the first time an immune- based, rather than a cancer-based, classification of tumours. Immune classification has been validated in other cancer types such as melanoma.

Hot immune tumours have next characteristics:high Immunoscore, checkpoint activation (PD-1, CTLA4, TIM3 and LAG3) or otherwise impaired T cell functions (for example, extracellular potassium- driven T cell suppression).

Altered-immunosuppressed immune tumours have next characteristics:intermediate Immunoscore, presence of soluble inhibitory mediators (TGFβ, IL-10 and VEGF), presence of immune suppressive cells (myeloid- derived suppressor cells and regulatory T cells), presence of T cell checkpoints (PD-1, CTLA4, TIM3 and LAG3).

Altered-excluded immune tumours have next characteristics: no T cell infiltration inside the tumour bed; intermediate Immunoscore, activation of oncogenic pathways, epigenetic regulation and reprogramming of the tumour microenvironment, aberrant tumour vasculature and/or stroma, hypoxia.

Cold immune tumours have next characteristics:low Immunoscore, failed T cell priming (low tumour mutational burden, poor antigen presentation and intrinsic insensitivity to T cell killing).

Four proposed types of tumour (hot, excluded, immunosuppressed and cold), based on Immunoscore, could be the first routine immune parameters to evaluate at the time of diagnosis. Recently, a novel theory of cancer evolution at the metastatic stage was demonstrated and highlighted a model of tumour evolution in which a parallel immune selection exists, with a major role of Immunoscore and T cells in this process. The fact that T cells are currently widely recognised as the key fighters in the antitumour battle makes the use of the Immunoscore an attractive option to help in guiding treatment selection.

The biggest challenge impeding the achievement of personalised cancer immunotherapies lies in the lack of a comprehensive knowledge of the cancer–immune interaction parameters; even when this knowledge is available, standardised methods of measuring most parameters are lacking.

Identification of key features, immune-related or tumour- related, at the moment of diagnosis is needed to build a solid classification strategy supporting subsequent therapy. In their article, the authors provide a panel of therapeutic strategies to be deployed or developed against hot, altered and cold tumours.

Given the pivotal role of T cells against cancer, the careful assessment of the pre-existing T cell landscape and of the immune microenvironment should be routinely used to differentiate specific cases, not only in the clinical setting but also at the preclinical stage. This information could help in the translation of study findings in clinical indications. The authors in particular discuss the impact of combination therapy on the immune response to convert an immune cold into a hot tumour.

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 and LabEx Immuno-oncology.

Immunoscore is a registered trademark from INSERM.



Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nature Reviews Drug Discovery 2019; 18(3):197–218.