Immune resilience in response to cancer therapy
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EDITORIAL
Immune resilience in response to cancer therapy Joanina K. Gicobi1 · Whitney Barham1 · Haidong Dong1 Published online: 4 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
The dynamic relationship between the immune system and cancer has been a topic of interest for decades. In 1909, Paul Ehrlich was the first to propose the hypothesis that host defense may prevent cancers from forming. Lewis Thomas and Frank Burnet later formalized this idea into the “immune surveillance theory,” suggesting that it is the immune system that constantly recognizes and deletes potential cancer cells throughout the body. Dunn and Schreiber then expanded this theory into the framework of “cancer immunoediting,” stating that if mutated cells do make it past the initial immune surveillance, they continue to interact with immune cells, first in equilibrium, and then eventually escaping the immune system’s control altogether to become a true malignancy. Tumor cells use multiple mechanisms to evade the host immune response such as secretion of immunosuppressive cytokines and recruitment of immunosuppressive cells. In addition, inhibitory molecule signaling and persistent antigen stimulation make tumor-reactive T cells dysfunctional or “exhausted” within the tumor microenvironment (TME). Exhausted T cells seem to abound within tumor tissues, having increased their inhibitory receptors, and decreased their cytokine production, proliferation, and effector molecule expression [1]. By the time a patient presents with a clinically detectable tumor, tumor surveillance has by definition failed and the original, effective, tumor-reactive immune cells can no longer be identified. They have become “invisible” [2]. However, the recent success of immune checkpoint inhibitor (ICI) therapy gives us a unique opportunity to re-visit the concept of “invisibility” of human tumor immunity. ICI therapy uses the patient’s own immunity to find and kill tumor cells, suggesting that there is still immune activity within the host that, if given the chance, can be extremely
* Haidong Dong [email protected] 1
Mayo Clinic College of Medicine and Science, Mayo Clinic, Rochester, MN, USA
effective. Thus, perhaps the invisible anti-tumor immune cells can be both identified and re-stimulated. This then leads to a critical question that remains unanswered with regard to ICI therapy: do checkpoint inhibitors work by resurrecting an immune response from once exhausted T cells? Or by expanding a remnant of effector T cells that never entered the exhausted state, but merely became suppressed and outnumbered? The answer to this question has significant implications for predicting the outcome of treatment, monitoring of clinical response, and for design of future combination therapies. For many years, we have assumed that clinical responses to ICI therapy were due to successful reinvigoration of the exhausted T cells in tumor tissues [1]. Thus, characterizing exhausted T-cell states has been a major focus of the immunotherapy field. Howe
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