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T cell responses to tumor: how dominant assumptions on immune activity led to a neglect of pathological functions, and how evolutionary considerations can help identify testable hypotheses for improving immunotherapy

Abstract

Cancer immunotherapy is based on the premise that activated, pro-inflammatory T cell responses to tumor will mostly combat tumor growth. Nowadays accepted as largely valid, this hypothesis has been formed as a result of extensive theoretical and experimental argumentation on the inherent function of the immune system and the nature of the immunological self, dating back to the foundations of immunology. These arguments have also been affected by how current working hypotheses were set by researchers, an issue that has been the focus of study by medical anthropologists. As a result of these processes, cancer immunotherapy has developed into a truly promising anti-cancer strategy, with very substantial benefits in clinical outcomes. However, as immunotherapy still has large margins for improvement, a more thorough examination of both the historical background and evolutionary context of current assumptions for how the immune system responds to cancer can help reveal novel, testable questions. We describe how attempting to answer some of these questions experimentally, such as identifying the contributors of tumor-associated fibrosis, has led to potentially useful insights on how to improve immunotherapy.

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Fig. 1

Abbreviations

FuHC:

Fusibility/histocompatibility gene product

RAG:

Recombination activating gene

Treg:

Regulatory T

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Acknowledgements

The author is indebted to Dr. A.G. Betz, Dr. D. Kallikourdis, and Prof. M. Holbraad for initiating discussions on the definition of immunological self and pregnancy, postulate identification in scientific theory, and medical anthropology, respectively. The author is also grateful to Prof. A. Mantovani, Prof. S. Meri, Dr. G.C. Ramos, and the reviewers for helpful suggestions and critical reading of the manuscript.

Funding

Aspects of the work described in this review received support from Associazione Italiana per la Ricerca su Cancro (AIRC) (MFAG10752), the Italian Ministry of Health (GR-2009-1558698 and GR-2013-02355011), Fondazione Veronesi as well as Fondazione Cariplo (2014-1184).

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Correspondence to Marinos Kallikourdis.

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The author declares to have no conflicts of interest.

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The data shown in this review have been authorized by the institutional animal welfare committee of the Humanitas Clinical and Research Center, as well as by the Italian Ministry of Health (authorization code 39/2014-PR).

Additional information

This paper is a Focussed Research Review based on a presentation given at the Fourteenth Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, held in Siena, Italy, 13th–15th October 2016. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Kallikourdis, M. T cell responses to tumor: how dominant assumptions on immune activity led to a neglect of pathological functions, and how evolutionary considerations can help identify testable hypotheses for improving immunotherapy. Cancer Immunol Immunother 67, 989–998 (2018). https://doi.org/10.1007/s00262-017-2113-9

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Keywords

  • Tumor
  • Immunotherapy
  • Immunological self
  • T cells
  • NIBIT 2016