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  • Review Article
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The secret ally: immunostimulation by anticancer drugs

Nature Reviews Drug Discovery volume 11, pages 215–233 (2012)Cite this article

Subjects

Key Points

  • Throughout the past century, conventional anticancer chemotherapeutics have been used based on their ability to selectively kill neoplastic cells while sparing their normal counterparts. More recently, targeted anticancer agents have been developed following the identification of cancer cell-specific molecular targets.

  • The classical notion that cancer constitutes a cell-autonomous genetic disease has progressively been invalidated, along with the understanding that the tumour microenvironment (including stromal and immune components) is a crucial determinant for tumour progression and response to therapy.

  • Local and systemic indicators of an ongoing response as well as biomarkers that predict the propensity of the immune system to engage in an anticancer immune response have been correlated with therapeutic outcome.

  • Several conventional and targeted anticancer chemotherapeutics can induce tumour-specific immune responses, either by triggering immunogenic cancer cell death or by eliciting innate or cognate immune effector mechanisms.

  • Conventional chemotherapeutics and targeted agents ameliorate the efficacy of several types of anticancer immunotherapy, including vaccination approaches and cytokine-mediated immunostimulation.

  • Immunochemotherapy currently appears to be a promising strategy for the eradication of cancer. It can be anticipated that the elucidation of the intricate crosstalk among cancer, stromal cells and immune cells will provide additional targets for anticancer therapy.

Abstract

It has recently become clear that the tumour microenvironment, and in particular the immune system, has a crucial role in modulating tumour progression and response to therapy. Indicators of an ongoing immune response, such as the composition of the intratumoural immune infiltrate, as well as polymorphisms in genes encoding immune modulators, have been correlated with therapeutic outcome. Moreover, several anticancer agents — including classical chemotherapeutics and targeted compounds — stimulate tumour-specific immune responses either by inducing the immunogenic death of tumour cells or by engaging immune effector mechanisms. Here, we discuss the molecular and cellular circuitries whereby cytotoxic agents can activate the immune system against cancer, and their therapeutic implications.

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Figure 1: Mechanisms through which conventional chemotherapeutics affect the immune system.
Figure 2: Mechanisms through which targeted anticancer agents affect the immune system.
Figure 3: Requirements for successful immunochemotherapy.

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Acknowledgements

The authors are supported by grants from the Ligue contre le Cancer (the French National League against Cancer), the AXA Chair for Longevity Research, Cancéropôle Ile-de-France, Institut National du Cancer (the French National Cancer Institute), the Bettencourt-Schueller Foundation, The Fondation de France, the Fondation pour la Recherche Médicale (the Foundation for Medical Research), the Agence National de la Recherche (the National Agency for Research) and the European Commission (APO-SYS, ArtForce, ChemoRes. Death-Train) as well as the LabEx Immuno-Oncology.

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Authors and Affiliations

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

    Lorenzo Galluzzi, Laura Senovilla, Laurence Zitvogel & Guido Kroemer

  2. Institut Gustave Roussy, Villejuif, F-94805, France

    Lorenzo Galluzzi, Laura Senovilla & Laurence Zitvogel

  3. Université Paris-Sud, Paris 11, Le Kremlin-Bicêtre, F-94276, France

    Lorenzo Galluzzi, Laura Senovilla & Laurence Zitvogel

  4. Center of Clinical Investigations in Biotherapies of Cancer (CICBT 507), Institut Gustave Roussy, Villejuif, F-94805, France

    Laurence Zitvogel

  5. Metabolomics Platform, Institut Gustave Roussy, Villejuif, F-94805, France

    Guido Kroemer

  6. Centre de Recherche des Cordeliers, Paris, F-75006, France

    Guido Kroemer

  7. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, F-75008, France

    Guido Kroemer

  8. Université Paris Descartes, Sorbonne Paris Cité, Paris, F-75006, France

    Guido Kroemer

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  1. Lorenzo Galluzzi
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  2. Laura Senovilla
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  3. Laurence Zitvogel
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  4. Guido Kroemer
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Correspondence to Guido Kroemer.

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Glossary

Proto-oncogenes

Genes that contribute to tumorigenesis via a gain-of-function mutation or overexpression.

Oncosuppressor genes

Genes that normally interfere with tumorigenesis. Deletion or loss-of-function mutations in these genes are permissive for the development of cancer.

Genome stability genes

Genes that control cell cycle progression or DNA repair mechanisms, thereby supervising the maintenance of genome stability.

Therapeutic monoclonal antibodies

A novel class of highly specific therapeutic agents that are used in various medical fields and often function by activating immune effector mechanisms.

Personalized medicine

A medical approach whereby therapies are tailored to each patient's pathological and genetic features to minimize side effects and improve efficacy.

Merkel cell carcinoma

A considerably rare human skin cancer of viral origin. Notably, the incidence of this cancer is particularly high, and the course of disease particularly aggressive, in immunocompromised individuals.

FOXP3

Forkhead box P3. A transcription factor from the FOX protein family that underlies the capacity of regulatory T cells to negatively regulate immune responses and favour self-tolerance (including in cancer).

T helper type 2 (TH2) response

The production — by CD4+ T helper lymphocytes — of cytokines including interleukin-4 (IL-4), IL-5 and IL-13 (which promote atopy), as well as IL-10 (which exerts immunosuppressive functions).

Activating NK receptor p30

(NKp30). Natural killer cell activating receptor encoded by the natural cytotoxicity triggering receptor 3 (NCR3) gene. The main endogenous ligand of NKp30 is the B7 homolog B7H6, which is selectively expressed on several distinct cancer cell types.

Metronomic chemotherapy

The chronic administration (at regular intervals) of chemotherapy at low, minimally toxic doses, with no prolonged drug-free periods.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells that are defined by their myeloid origin, immature state and their ability to potently suppress T cell responses.

Signal transducer and activator of transcription

(STAT). The mammalian genome encodes at least seven distinct members of the STAT family of transcription factors, which regulate multiple aspects of cell growth, survival and differentiation.

T helper type 1 (TH1) antitumour response

The production — by CD4+ T helper lymphocytes — of cytokines, mainly interferon-γ and lymphotoxin-α, which exert immunostimulatory functions.

OX40

A cell surface glycoprotein of the tumour necrosis factor receptor superfamily that, upon binding to its ligand (OX40L, which is expressed on activated antigen-presenting cells), delivers a co-stimulatory signal that is essential for the long-term survival of CD4+ T cells.

γδ T cells

A small subset of T cells that possess an invariant T cell receptor on their surface and operate at the boundary between innate and adaptive immunity.

4T1-Neu

Murine breast cancer cells (syngenic to BALB/c mice) that are transduced to express the rat Neu gene (the rat orthologue of human HER2; also known as ERBB2).

SNARE

Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein (SNAP) receptor.

CD20+CD5+sIgM+ B lymphocytes

B lymphocytes expressing at their surface CD5, CD20 and immunoglobulin M (IgM) molecules.

Indoleamine 2,3-dioxygenase

An enzyme that catalyses the degradation of the essential amino acid L-tryptophan to N-formylkynurenine, which is an immunosuppressive metabolite.

Phosphoinositide 3-kinases

(PI3Ks). A family of kinases that encompasses three distinct classes of lipid kinases that can be discriminated based on primary structure, substrate specificity and regulation. PI3Ks regulate an extraordinarily diverse group of cellular functions.

BH3 mimetic

A small, plasma membrane-permeant chemical that is structurally similar to the BCL-2 homology 3 (BH3) domain of pro-apoptotic BCL-2 family members.

Antibody-dependent cellular cytotoxicity

The process whereby an effector cell of the innate immune system (for example, a natural killer cell) kills a target cell that has been bound by specific antibodies.

Antibody-dependent cellular phagocytosis

The process whereby a phagocytic cell of the innate immune system (for example, a macrophage) takes up and degrades a target cell that has been bound by specific antibodies.

Complement-dependent cytotoxicity

The activation of the complement cascade against a target cell that has been bound by specific antibodies, leading to the formation of a membrane attack complex and cell lysis.

CD40

A co-stimulatory molecule (the receptor for the CD40 ligand; also known as CD154) that is expressed by antigen-presenting cells and required for their activation.

Inhibitor of apoptosis proteins

A family of functionally and structurally related proteins that inhibit caspase activation but also exert E3 ubiquitin ligase activity following death receptor ligation.

Histone deacetylase inhibitors

A class of compounds that interfere with the function of histone deacetylases, thereby affecting the epigenetic regulation of transcription.

Exosome-based vaccines

Anticancer vaccines that are based on 30–90 nm vesicles originating from late endosomes. These vesicles are secreted by professional antigen-presenting cells and, because of their composition, they exert profound immunostimulatory functions.

Wilms' tumour 1

A transcription factor encoded by the Wilms' tumour 1 (WT1) gene that has an essential role in the normal development of the urogenital system.

NY-ESO-1

A highly immunogenic cancer–testis antigen that is widely used in clinical cancer vaccine trials.

Fibroblast activation protein-α

A transmembrane serine protease that is induced on reactive stromal fibroblasts in epithelial cancers, sarcomas and granulation tissue, and may be involved in tumour invasion, tissue remodelling and wound repair.

Oncogene addiction

The phenomenon whereby cancer cells depend on the continuous hyperactivation of one or more oncogenes for their survival.

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Galluzzi, L., Senovilla, L., Zitvogel, L. et al. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 11, 215–233 (2012). https://doi.org/10.1038/nrd3626

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