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  • Review Article
  • Published:

Immunological aspects of cancer chemotherapy

Nature Reviews Immunology volume 8, pages 59–73 (2008)Cite this article

Key Points

  • The dominant rationale to generate new (and to assess old) anticancer chemotherapeutic agents is to determine their cell-autonomous effects — that is, their capacity to reduce the growth (cytostasis) and to induce the death (cytotoxicity) of tumour cells in vitro and in vivo (usually in immunodeficient mice that have been xenotransplanted with human tumours). Experimental data obtained from immuncompetent mice and clinical data obtained from patients indicate that several chemotherapeutic agents have unexpected effects on the immune system. At least in some instances, these 'side effects' can contribute to the therapeutic effects of anticancer drugs.

  • A non-exhaustive list of examples of drugs that combine anticancer and immunostimulatory effects includes: imatinib mesylate, cyclophosphamide, anthracyclines and 5-fluorouracil.

  • Imatinib mesylate, a protein tyrosine kinase inhibitor, can induce caspase-independent death of tumour cells, can enhance natural killer (NK)-cell activities and can induce the expansion of a specific NK-cell subset that also bears dendritic-cell markers, known as interferon-producing killer dendritic cells, which in turn have tumoricidal effects.

  • Cyclophosphamide, a DNA-alkylating agent, induces non-apoptotic cell death of tumour cells and T cells. In addition, it can deplete regulatory T cells, thereby overriding their antitumour immune responses.

  • Anthracyclines can induce an immunogenic variant of apoptosis in tumour cells, thereby eliciting an antitumour immune response that is mediated by dendritic cells and cytotoxic T cells.

  • 5-Fluorouracil and other p53-activating cytotoxic drugs promote increased expression of tumour-associated antigens and co-stimulatory molecules on tumour cells.

  • These agents illustrate the therapeutic feasibility of an 'immunogenic chemotherapy'; that is, a programme of chemotherapy that aims at stimulating the antitumour immune response as a warranted side effect of the therapy. Moreover, it might be possible to combine agents that induce direct cancer-cell-specific and immunostimulatory effects for an optimal therapeutic outcome.

  • Theoretically, the induction of immunogenic cancer-cell death or other immunogenic effects should be one of the aims of anticancer chemotherapy so that the immune system can contribute through a 'bystander effect' to eradicate chemotherapy-resistant cancer cells and cancer stem cells.

Abstract

Accumulating evidence indicates that the innate and adaptive immune systems make a crucial contribution to the antitumour effects of conventional chemotherapy-based and radiotherapy-based cancer treatments. Moreover, the molecular and cellular bases of the immunogenicity of cell death that is induced by cytotoxic agents are being progressively unravelled, challenging the guidelines that currently govern the development of anticancer drugs. Here, we review the immunological aspects of conventional cancer treatments and propose that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies.

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Figure 1: Sequential events that link tumour-cell stress with activation of antigen-presenting cells.
Figure 2: Linking tumour-cell stress and effector-cell killing.
Figure 3: Reconciling host and tumour requirements for optimal management of cancer patients.

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Acknowledgements

The authors are supported by grants from the Ligue Nationale contre le Cancer (L.Z., G.K. and L.A.), the European Union (ALLOSTEM, DC-THERA; L.Z.), Cancéropôle Île-de-France, Institut National du Cancer and Agence Nationale pour la Recherche (G.K.). F.G. is supported by a Poste d'acceuil INSERM.

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Authors and Affiliations

  1. INSERM, U805, Institut Gustave Roussy, 39 Rue Camille Desmoulins, Villejuif, F-94805, Paris, France

    Laurence Zitvogel, Lionel Apetoh & François Ghiringhelli

  2. CIC BT507, Institut Gustave Roussy, 39 Rue Camille Desmoulins, Villejuif, F-94805, Paris, France

    Laurence Zitvogel & François Ghiringhelli

  3. Faculté de Médecine Paris Sud-Université Paris XI, 63 Rue Gabriel Péri, Le Kremlin Bic^tre Cedex, 94276, France

    Laurence Zitvogel, Lionel Apetoh, François Ghiringhelli & Guido Kroemer

  4. Centre Georges-François Leclerc, 1 Rue du Professeur Marion, Dijon, 21000, France

    François Ghiringhelli

  5. INSERM, U848, Institut Gustave Roussy, Pavillon de Recherche 1, 39 Rue Camille Desmoulins, Villejuif, F-94805, Paris, France

    Guido Kroemer

Authors
  1. Laurence Zitvogel
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  2. Lionel Apetoh
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  3. François Ghiringhelli
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  4. Guido Kroemer
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Correspondence to Laurence Zitvogel or Guido Kroemer.

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FURTHER INFORMATION

Institut Gustave-Roussy

Glossary

Cancer stem cells

A small population of undifferentiated cells from which the differentiating cancer cells originate. These cells are suspected to account for relapse after conventional therapy.

Oncogene

A gene of which the overexpression or gain-of-function mutation contributes to oncogenesis.

Tumour-suppressor gene

A gene that, when eliminated or inactivated, is permissive for the development of cancers. These genes often determine cell-cycle checkpoints or facilitate induction of programmed cell death.

Genome-stability genes

Genes that control cell-cycle advancement and/or DNA repair to allow for the maintenance of genome stability.

Neoplasia

From the Greek for 'new formations'. New growths or tumours, which can be malignant.

Pattern-recognition receptors

Host receptors (such as Toll-like receptors) that are able to sense pathogen-associated molecular patterns and initiate signalling cascades (involving activation of nuclear factor-κB) that lead to an innate immune response.

TH1 cells

(T helper 1 cells). Among the two well-described subsets of activated CD4+ T cells, TH1 cells produce interferon-γ and tumour-necrosis factor and enhance cell-mediated immunity. TH2 cells produce interleukin-4 (IL-4), IL-5 and IL-13, supporting humoral immunity and counteracting TH1-cell responses.

NKG2D

(Natural-killer group 2, member D). A lectin-type activating receptor encoded by the natural killer (NK)-cell gene complex and expressed on the surface of NK, NKT, γδ T cells and some cytolytic CD8+ αβ T cells. NKG2D ligands are MHC-class-I-polypeptide-related sequence A (MICA) and MICB in humans, as well as retinoic acid early transcript 1 (RAE1) and H60 in mice. Such ligands are generally expressed at the cell surface of infected, stressed or transformed cells.

Endoplasmic reticulum stress

(ER stress). A response by the ER that results in the disruption of protein folding and in the accumulation of unfolded proteins in the ER.

Eat-me signal

A signal emitted by dying cells to facilitate their recognition and phagocytosis by neighbouring healthy cells.

Isolated limb perfusion

(ILP). A surgical technique consisting of injection of chemotherapeutic agents into the artery of an extremity while the venous outflow is recovered, thus avoiding systemic drug effects.

p53

A major transcription factor that is activated by numerous genotoxic insults to induce cell-cycle arrest, cellular senescence or apoptosis. p53 is frequently mutated or functionally inactivated in cancer.

DNA-damage response

A cellular response that is usually elicited by DNA-damaging agents (such as ionizing irradiation or mutagenic chemicals) and involves the activation of DNA-damage foci (with phosphorylated histone H2AX as a hallmark). The DNA-damage response elicits cell-cycle arrest, DNA repair or apoptosis.

NKT cells

(Natural-killer T cells). A heterogeneous subset of T cells that are characterized by the co-expression of semi-invariant T-cell receptor (TCR) α-chains together with NK-cell markers.

Senescence

A nearly irreversible stage of permanent G1 cell-cycle arrest, linked to morphological changes (flattening of the cells), metabolic changes and changes in gene expression (with expression of senescence-associated β-galactosidase), the induction of which depends on p53 and cell-cycle-blockers such as p21 and p16.

Abscopal effects

Distant antitumour effects seen after local radiation therapy.

TReg cell

(Regulatory T cell). A specialized type of CD4+ T cell that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance and are characterized by the expression of CD25 (also known as the α-chain of the interleukin-2 receptor) and the transcription factor forkhead box P3 (FOXP3).

HER2

(Human epidermal growth-factor receptor 2). A receptor protein-tyrosine kinase that is overexpressed in a subset of human breast cancers.

3LL tumour model

3LL is a non-small-cell lung cancer cell line that grows in vivo after injection into C57BL/6 syngenic hosts.

Myeloid suppressor cells

A group of immature CD11b+GR1+ cells (which include precursors of macrophages, granulocytes, dendritic cells and myeloid cells) that are produced in response to various tumour-derived cytokines. These cells have been shown to induce tumour-associated antigen-specific CD8+ T-cell tolerance.

Myelodysplastic syndrome

A pre-neoplastic syndrome characterized by a hypercellular bone marrow with reduced haematopoietic capacity.

Vascular-disrupting agents

In contrast to anti-angiogenic approaches, which aim to prevent the neovascularization processes in tumours, vascular-disrupting agents aim to cause the rapid and selective shutdown of the established tumour vasculature, leading to secondary tumour-cell death.

Angiogenesis

The development of new blood vessels from existing blood vessels. It is frequently associated with tumour development and inflammation.

IKDCs

(Interferon-producing killer dendritic cells). Isolated in mouse models only, these cells express both NK-cell and B-cell markers but lack plasmacytoid DC- and T-cell-specific, and co-stimulatory molecules. They react to a large variety of tumour cells by producing interferon-γ and killing the tumour cells without exogenous stimulation.

Death receptors

A family of cell-surface receptors capable of mediating cell death on ligand-induced trimerization. The best-studied members include tumour-necrosis factor receptor 1 (TNFR1), FAS (or CD95, which binds FAS ligand) and two receptors for TNF-related apoptosis-inducing ligand (TRAILR1 and TRAILR2).

Cross-priming

Initiation of a CD8+ T-cell response against an antigen that is not present in antigen-presenting cells (APCs). The antigen must be taken up by APCs and then re-routed to the MHC class I presentation pathway.

Small interfering RNAs

(siRNA). Synthetic RNA molecules of 19–23 nucleotides that are used to 'knock down' (that is, to silence the expression of) a specific gene. This is known as RNA interference (RNAi) and is mediated by the sequence-specific degradation of mRNA.

Neoadjuvant therapy

Radiotherapy and chemotherapy before surgical resection of the tumour.

Adjuvant therapy

Radiotherapy and chemotherapy after surgical resection of the primary tumour.

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Zitvogel, L., Apetoh, L., Ghiringhelli, F. et al. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8, 59–73 (2008). https://doi.org/10.1038/nri2216

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