Challenges and developing solutions for increasing the benefits of IL-2 treatment in tumor therapy

Abstract

Interleukin-2 (IL-2) is a cytokine with pleiotropic effects on the immune system. Systemic IL-2 treatment has produced durable responses in melanoma and renal cancer patients, but unfortunately this is effective only in a fraction of patients. Moreover, IL-2 treatment also engenders serious side effects, which limit its clinical utility. It is now appreciated that IL-2 not only stimulates NK and effector T cells but also has a critical role in the generation and maintenance of regulatory T cells, which act to dampen immune responses. Thus, successful immunotherapy of cancers using IL-2 has to address two fundamentally important issues: (1) how to limit side effects yet be active where it is needed, and (2) how to preferentially activate effector T cells while limiting the stimulation of Tregs. Strategies are now being developed to address these critical obstacles that may lead to a renaissance of IL-2 therapy.

Keywords::

• IL-2
• IL-2 receptor
• immune response
• tumor immunotherapy
• tumor microenvironment

Acknowledgements

The authors would like to thank our colleagues for helpful suggestions to the manuscript. The authors want to also acknowledge generous support from Steven and Alison Krausz and from FC Blodgett. The authors would also like to acknowledge all those who contributed to the study of IL-2 and its use for immunotherapy. Unfortunately due to space constraints, the authors could not cite all contributors to this field that has spanned many years.

Financial & competing interests disclosure

D Skrombolas was supported in part by the National Institutes of Health Training Grant AI07285. The project described in this publication was supported in part by the University of Rochester CTSA award number UL1 TR000042 from the National Center for Advancing Translational Sciences of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• IL-2 has pleiotropic effects on the immune system.

• IL-2, like many cytokines, has evolved to act locally in a paracrine or autocrine fashion.

• High-dose systemic IL-2 can be extremely effective in a fraction of cancer patients.

• Different immune cell subsets express different combinations and amounts of the IL-2 receptors.

• Activated effector T cells and Tregs both express the α chain component of the high-affinity IL-2 receptor.

• IL-2 has dual opposing effects on immune responses by promoting NK cells and T effector cells but also enhancing Tregs.

• Establishing new strategies that preferentially target specific immune cell subsets are critical.

• Finding ways to deliver IL-2 systemically while avoiding unwanted side effects will be essential in developing effective tumor therapy.

Notes