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.