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Mechanisms driving the immunoregulatory function of cancer cells

Nature Reviews Cancer volume 23, pages 193–215 (2023)Cite this article

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Abstract

Tumours display an astonishing variation in the spatial distribution, composition and activation state of immune cells, which impacts their progression and response to immunotherapy. Shedding light on the mechanisms that govern the diversity and function of immune cells in the tumour microenvironment will pave the way for the development of more tailored immunomodulatory strategies for the benefit of patients with cancer. Cancer cells, by virtue of their paracrine and juxtacrine communication mechanisms, are key contributors to intertumour heterogeneity in immune contextures. In this Review, we discuss how cancer cell-intrinsic features, including (epi)genetic aberrations, signalling pathway deregulation and altered metabolism, play a key role in orchestrating the composition and functional state of the immune landscape, and influence the therapeutic benefit of immunomodulatory strategies. Moreover, we highlight how targeting cancer cell-intrinsic parameters or their downstream immunoregulatory pathways is a viable strategy to manipulate the tumour immune milieu in favour of antitumour immunity.

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Fig. 1: Overview of how cancer cell-intrinsic parameters regulate immune cell behaviour.
Fig. 2: Cancer genotype–immunophenotype relationships.
Fig. 3: Cancer cell-intrinsic epigenetic regulation of the cancer cell–immune cell crosstalk.
Fig. 4: Cancer cell-intrinsic signalling dictates the tumour immune microenvironment.
Fig. 5: Metabolic reprogramming of cancer cells affects immune behaviour.

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Acknowledgements

Research in the K.E.d.V. laboratory is funded by the Netherlands Organization for Scientific Research (grant NWO-VICI 91819616), the Dutch Cancer Society (KWF10623, KWF13191 and KWF14339) and the Oncode Institute. The authors thank K. Kos, D. Duits, H. Garner and C. Burrello for their insightful input and all members of the K.E.d.V. laboratory for valuable discussions.

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Authors and Affiliations

  1. Division of Tumour Biology & Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands

    Antoinette van Weverwijk & Karin E. de Visser

  2. Department of Immunology, Leiden University Medical Centre, Leiden, Netherlands

    Karin E. de Visser

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  1. Antoinette van Weverwijk
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  2. Karin E. de Visser
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Both authors researched data for the article, contributed substantially to discussion of the content and wrote the article. K.E.d.V. reviewed and edited the manuscript before submission.

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Correspondence to Karin E. de Visser.

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K.E.d.V. reports research funding from Roche/Genentech and is a consultant for Macomics. A.v.W. declares no competing interests.

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Nature Reviews Cancer thanks Davide Bedognetti, who co-reviewed with Jessica Roelands; Hiroyoshi Nishikawa; and Stefani Spranger for their contribution to the peer review of this work.

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Glossary

Autophagy

An intracellular recycling process that selectively degrades damaged proteins, lipids, nucleic acids, metabolites and organelles to maintain cell homeostasis and viability.

Cancer immune landscape

The composition, location, phenotype and functional state of immune cells in tumours.

Cancer immunotherapy

Therapeutic interventions that activate or suppress aspects of the immune system, including immune checkpoint blockade, to treat cancer.

Cytotoxic T lymphocytes

(CTLs). A group of antigen-specific T cells that have the capacity to directly target and destroy cells that express the cognate antigen on their surface, presented by major histocompatibility complex molecules.

Exosomes

Small endosomal-derived lipid bilayer membrane vesicles that carry cargo to target cells they encounter, which results in reprograming of recipient cells distal from their release.

Extracellular vesicles

Small lipid-enclosed vesicles, including microvesicles, exosomes and apoptotic bodies, that carry cellular cargo such as DNA, RNA, protein or lipids that can be taken up by other cells, where the release of the extracellular vesicle cargo can modulate cell function.

Immune checkpoint molecules

Co-stimulatory or co-inhibitory receptors and their ligands that exert stimulatory or inhibitory effects, respectively, on immune responses and that function as ‘gatekeepers’ by balancing immune cell activation and inhibition.

Immune escape

A variety of strategies that are exploited by cancer cells to avoid discovery and destruction by the immune system.

Microsatellites

Short sequences of DNA (one to ten nucleotides) that are tandemly repeated in the genome.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of myeloid cells, consisting of (immature) monocytic and neutrophilic cells with immunosuppressive capacities.

Polarization

A state of functional activation of a myeloid immune cell in response to specific environmental and tumour-derived signals to induce, for example, the immunostimulatory M1-like or immunosuppressive M2-like polarization of macrophages.

Tumour microenvironment

(TME). The environment around the tumour, that besides cancer cells is composed of a large diversity of host cells, including immune cells, fibroblasts and endothelial cells, as well as extracellular matrix components, blood vessels and signalling molecules, such as chemokines, cytokines and growth factors.

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van Weverwijk, A., de Visser, K.E. Mechanisms driving the immunoregulatory function of cancer cells. Nat Rev Cancer 23, 193–215 (2023). https://doi.org/10.1038/s41568-022-00544-4

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