Nobel Prize for immune checkpoint inhibitors, understanding the immunological switching between immunosuppression and autoimmunity

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) are a revolutionary form of immunotherapy in cancer. However, the percentage of patients responding to therapy is relatively low, while adverse effects occur in a large number of patients. In addition, the therapeutic mechanisms of ICIs are not yet completely described.

Areas covered

The initial view (articles published in PubMed, Scopus, Web of Science, etc.) was that ICIs increase tumor-specific immunity. Recent data (collected from the same databases) suggest that the ICIs pharmacotherapy actually extends beyond the topic of immune reactivity, including additional immune pathways, such as disrupting immunosuppression and increasing tumor-specific autoimmunity. Unfortunately, there is no clear delimitation between these specific autoimmune reactions that are therapeutically beneficial, and nonspecific autoimmune reactions/toxicity that can be extremely severe side effects.

Expert opinion

Immune checkpoint mechanisms perform a non-selective immune regulation, maintaining a dynamic balance between immunosuppression and autoimmunity. By blocking these mechanisms, ICIs actually perform an immunological reset, decreasing immunosuppression and increasing tumor-specific immunity and predisposition to autoimmunity. The predisposition to autoimmunity induces both side effects and beneficial autoimmunity. Consequently, further studies are necessary to maximize the beneficial tumor-specific autoimmunity, while reducing the counterproductive effect of associated autoimmune toxicity.

KEYWORDS:

• Immune checkpoint inhibitors
• immunosuppression
• tumor-specific immunity
• tumor-specific autoimmunity
• immunological switch between immunosuppression and autoimmunity

Article highlights

• ICIs perform an immunological switching between immunosuppression and autoimmunity, decreasing immunosuppression and increasing predisposition to autoimmunity

• This immunological switch induces three distinct but interrelated pharmacological mechanisms:

• Increased tumor-specific immunity

• Increased tumor-specific autoimmunity (beneficial/therapeutic autoimmunity)

• Inducing common/non-specific autoimmunity (side effects related to healthy tissues)

This box summarizes key points contained in the article.

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript reports the following conflicts and disclosures in the past 36 months: advisory board for BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, and Infinity Pharmaceuticals; research support to institution from Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine, and BMS; steering committee of studies for BMS, Bavarian Nordic, Seattle Genetics, QED, G1 Therapeutics (all unpaid), and Astrazeneca, EMD Serono, and Debiopharm (paid); data safety monitoring committee for Mereo; travel costs from BMS, and Astrazeneca; writing/editor fees from Uptodate, and Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; speaking fees from Physicians Education Resource (PER), Onclive, Research to Practice, Medscape, Cancer Network, and Masters Lecture Series (MLS). All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.