Resistance Mechanisms to Anti-PD Cancer Immunotherapy

Author:

Vesely Matthew D.12,Zhang Tianxiang1,Chen Lieping123

Affiliation:

1. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA;

2. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA

3. Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut, USA

Abstract

The transformative success of antibodies targeting the PD-1 (programmed death 1)/B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction of patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, and the reason for failure in other patients is less known. By dissecting the mechanisms underlying this resistance, current studies reveal that the tumor microenvironment is a major location for resistance to occur. Furthermore, the resistance mechanisms appear to be highly heterogeneous. Here, we discuss recent human cancer data identifying mechanisms of resistance to anti-PD therapy. We review evidence for immune-based resistance mechanisms such as loss of neoantigens, defects in antigen presentation and interferon signaling, immune inhibitory molecules, and exclusion of T cells. We also review the clinical evidence for emerging mechanisms of resistance to anti-PD therapy, such as alterations in metabolism, microbiota, and epigenetics. Finally, we discuss strategies to overcome anti-PD therapy resistance and emphasize the need to develop additional immunotherapies based on the concept of normalization cancer immunotherapy.

Publisher

Annual Reviews

Subject

Immunology,Immunology and Allergy

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