Immunogenic Cell Death in Cancer Therapy

Kroemer, Guido; Galluzzi, Lorenzo; Kepp, Oliver; Zitvogel, Laurence

doi:10.1146/annurev-immunol-032712-100008

Cited by 2,604 publications

(2,490 citation statements)

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“…In contrast, depletion of CTLs using anti-CD8a antibodies completely abrogated the antitumor effects of anthracyclines (Figures 4a and b), confirming their contribution to the efficacy of chemotherapy. 13 Hence, genetic deficiency or antibody-induced depletion of B lymphocytes did not interfere with the therapeutic activity of anthracyclines.…”

Section: Contribution Of Cytotoxic T Cells But Not Of B Lymphocytes Tmentioning

confidence: 99%

“…'Immunogenic cell death'(ICD) can be defined as a process, in which cell death is preceded by a preapoptotic endoplasmic reticulum (ER) stress response and autophagic program, facilitating the recruitment, activation and antigen-presenting function of DCs. 13 Indeed, ICD is accompanied by exposure or secretion of cell death-associated molecular patterns, such as calreticulin (CRT) (for the engulfment of dead bodies by DC), high-mobility group Box-1 (HMGB1) (for the Toll-like receptor 4/myeloid differentiation primary response genedependent processing of the phagocytic cargo by DC) and ATP (for DC recruitment and the Nlrp3-dependent IL-1b release culminating in Tc1 polarization). 13 Accordingly, after exposure to neoadjuvant chemotherapy, approximately one-third of stage 2/ 3 breast cancers appeared highly infiltrated by cytotoxic T cells, with a concomitant reduction of B lymphocytes and Th2 cells.…”

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confidence: 99%

“…13 Indeed, ICD is accompanied by exposure or secretion of cell death-associated molecular patterns, such as calreticulin (CRT) (for the engulfment of dead bodies by DC), high-mobility group Box-1 (HMGB1) (for the Toll-like receptor 4/myeloid differentiation primary response genedependent processing of the phagocytic cargo by DC) and ATP (for DC recruitment and the Nlrp3-dependent IL-1b release culminating in Tc1 polarization). 13 Accordingly, after exposure to neoadjuvant chemotherapy, approximately one-third of stage 2/ 3 breast cancers appeared highly infiltrated by cytotoxic T cells, with a concomitant reduction of B lymphocytes and Th2 cells. 14 Moreover, the relative proportions of macrophages and CD8 þ T cells predict the pathological responses to neoadjuvant anthracycline-based therapy and overall survival in locally advanced breast cancer.…”

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confidence: 99%

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Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4 þ and CD8 þ T cells producing interferon-c. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-celldepleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.

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Section: Contribution Of Cytotoxic T Cells But Not Of B Lymphocytes Tmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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“…To this end, numerous approaches have been proposed to potentiate responses to immunotherapy including combination treatment with various immune-modulating drugs, or co-treatment with chemotherapy or radiotherapy. 5–7 A better understanding of the context in which checkpoint inhibitors are successful, and new strategies to make them more effective, are needed to fully realize the potential of these promising new drugs.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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“…9,20,21,260 Such knowledge has been instrumental for the development of a wide panel of therapeutic interventions that specifically aim at (re)establishing anticancer immunosurveillance (rather than merely causing the death of malignant cells), including peptide-based vaccination. 8,105,176,261-264 Unfortunately, it has soon become clear that the majority of immunotherapies developed so far is poorly active when employed as standalone therapeutic intervention, largely reflecting (1) natural and treatment-driven immunoediting, resulting in the selection of poorly immunogenic cancer cell populations; 115,265,266 and (2) the robust immunosuppression established by malignant cells, both locally and systemically.…”

Section: Discussionmentioning

confidence: 99%

Trial watch: Peptide-based vaccines in anticancer therapy

et al. 2018

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Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen

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Immunogenic Cell Death in Cancer Therapy

Cited by 2,604 publications

References 110 publications

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Trial watch: Peptide-based vaccines in anticancer therapy

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