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  • Perspective
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Beneficial autoimmunity improves cancer prognosis

Nature Reviews Clinical Oncology volume 18, pages 591–602 (2021)Cite this article

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Abstract

Many tumour antigens that do not arise from cancer cell-specific mutations are targets of humoral and cellular immunity despite their expression on non-malignant cells. Thus, in addition to the expected ability to detect mutations and stress-associated shifts in the immunoproteome and immunopeptidome (the sum of MHC class I-bound peptides) unique to malignant cells, the immune system also recognizes antigens expressed in non-malignant cells, which can result in autoimmune reactions against non-malignant cells from the tissue of origin. These autoimmune manifestations include, among others, vitiligo, thyroiditis and paraneoplastic syndromes, concurrent with melanoma, thyroid cancer and non-small-cell lung cancer, respectively. Importantly, despite the undesirable effects of these symptoms, such events can have prognostic value and correlate with favourable disease outcomes, suggesting ‘beneficial autoimmunity’. Similarly, the occurrence of dermal and endocrine autoimmune adverse events in patients receiving immune-checkpoint inhibitors can have a positive predictive value for therapeutic outcomes. Neoplasias derived from stem cells deemed ‘not essential’ for survival (such as melanocytes, thyroid cells and most cells in sex-specific organs) have a particularly good prognosis, perhaps because the host can tolerate autoimmune reactions that destroy tumour cells at some cost to non-malignant tissues. In this Perspective, we discuss examples of spontaneous as well as therapy-induced autoimmunity that correlate with favourable disease outcomes and make a strong case in favour of this ‘beneficial autoimmunity’ being important not only in patients with advanced-stage disease but also in cancer immunosurveillance.

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Fig. 1: Hypothetical link between the immunosurveillance of non-malignant and malignant cells.
Fig. 2: Relationship between patient survival and the cancer cell of origin.
Fig. 3: Defining features of a curative response to cancer immunotherapies.

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Acknowledgements

We thank V. Carbonnier (Centre de Recherche des Cordeliers, Paris, France) for help in preparing Fig. 2. L.Z. and G.K. receive support from the Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Ruban Rose”; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085); Inserm (HTE); Institut National du Cancer (INCa); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); Ligue contre le Cancer (équipe labellisée); RHU Torino Lumière; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. C.P. receives support from the Canadian Cancer Society (#705604) and the Canadian Institutes of Health Research (FDN 148400). O.J.F. receives support from the University of Pittsburgh Medical Center (UPMC) Immune Transplant and Therapy Center (ITTC) and the US National Cancer Institute (grant 5R35CA210039).

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Authors and Affiliations

  1. Gustave Roussy Comprehensive Cancer Institute, Villejuif, France

    Laurence Zitvogel & Guido Kroemer

  2. Université Paris Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France

    Laurence Zitvogel

  3. INSERM U1015, Gustave Roussy, Villejuif, France

    Laurence Zitvogel

  4. Equipe labellisée par la Ligue contre le cancer, Villejuif, France

    Laurence Zitvogel

  5. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) BIOTHERIS, Villejuif, France

    Laurence Zitvogel

  6. Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China

    Laurence Zitvogel & Guido Kroemer

  7. Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada

    Claude Perreault

  8. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Olivera J. Finn

  9. Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France

    Guido Kroemer

  10. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

    Guido Kroemer

  11. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  12. Karolinska Institute, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden

    Guido Kroemer

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  1. Laurence Zitvogel
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  4. Guido Kroemer
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Contributions

G.K. researched data for the manuscript, L.Z. and G.K. wrote it with the input of C.P. and O.J.F., and all authors edited and reviewed the manuscript before submission.

Corresponding authors

Correspondence to Laurence Zitvogel or Guido Kroemer.

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Competing interests

L.Z. and G.K. are founders of EverImmune. G.K. is a founder of Samsara Therapeutics and Therafast Bio. O.J.F. is a consultant for Biovelocita, GeoVax, Immodulon, Iaso Therapeutics and PDS Biotech. C.P. declares no competing interests.

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Nature Reviews Clinical Oncology thanks S. Karagiannis, R. Liblau, H-G. Rammensee and J. Yewdell for their contribution to the peer review of this work.

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Glossary

Antigen spreading

Expansion of the immune response to secondary epitopes that were not part of the initial recognition process.

Danger-associate molecular patterns

(DAMPs). Protein exposed on the surface of stressed cells or metabolite or protein released from stressed or dying cells that alerts immune effectors.

Disease-associated antigens

Self-molecules that undergo changes in levels of expression and post-translational modifications in cells infected with pathogens, subjected to acute inflammation or during malignant transformation.

Immunopeptidome

Sum of peptides bound to MHC class I molecules that can be recognized by T cell receptors.

Immune-related adverse events

(irAEs). Undesired adverse events of immune-checkpoint inhibitors caused by excessive activation of autoimmune responses.

Lambert–Eaton myasthenic syndrome

Myasthenia-like condition in which an autoimmune response to the neuromuscular junctions causes progressive muscle weakness. Half of the diagnoses occur in patients with small-cell lung cancer.

Medullary thymic epithelial cells

(mTECs). Specialized cells that present self-antigens to induce clonal deletion of self-specific T lymphocytes, thus assuring central tolerance.

Melanocytes

Specialized cells found in the basal skin layer that produce melanin and transfer this pigment in the form of melanosomes into the cytoplasm of adjacent keratinocytes.

Paraneoplastic syndromes

Compendium of clinical signs provoked by a cancer at a distant location, generally as a result of autoimmune responses.

Senescence

Close-to-irreversible blockade of the cell cycle coupled to a major loss of cell function that occurs in response to injury or as a result of aging.

Thyrocyte

Thyroid epithelial cell producing thyroid hormones.

Tumour-associated antigens

Antigens that can be found on non-malignant cells but whose (over)expression on the surface of cancer cells enables the immune system to distinguish such cells from their non-transformed counterparts.

Tumour-specific antigens

Antigens that are uniquely present within or on a cancer cell. They can arise via both mutational (mutated tumour-specific antigens) and non-mutational (non-mutated tumour-specific antigens) mechanisms.

Vitiligo

Also known as leukoderma. White patches of the skin caused by the autoimmune destruction of melanocytes.

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Zitvogel, L., Perreault, C., Finn, O.J. et al. Beneficial autoimmunity improves cancer prognosis. Nat Rev Clin Oncol 18, 591–602 (2021). https://doi.org/10.1038/s41571-021-00508-x

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