Abstract
Disruption of the programmed cell death protein 1 (PD-1) pathway with immune checkpoint inhibitors represents a major breakthrough in the treatment of non-small cell lung cancer. We hypothesized that combined inhibition of C5a/C5aR1 and PD-1 signaling may have a synergistic antitumor effect. The RMP1-14 antibody was used to block PD-1, and an L-aptamer was used to inhibit signaling of complement C5a with its receptors. Using syngeneic models of lung cancer, we demonstrate that the combination of C5a and PD-1 blockade markedly reduces tumor growth and metastasis and leads to prolonged survival. This effect is accompanied by a negative association between the frequency of CD8 T cells and myeloid-derived suppressor cells within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. Our study provides support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer.Significance: Using a variety of preclinical models of lung cancer, we demonstrate that the blockade of C5a results in a substantial improvement in the efficacy of anti-PD-1 antibodies against lung cancer growth and metastasis. This study provides the preclinical rationale for the combined blockade of PD-1/PD-L1 and C5a to restore antitumor immune responses, inhibit tumor cell growth, and improve outcomes of patients with lung cancer. Cancer Discov; 7(7); 694-703. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.
Highlights
Immunotherapy based on checkpoint inhibitors has emerged as a potent tool for the treatment of lung cancer, the leading cause of cancer-related death worldwide
No differences were observed in the frequencies of CD4 T cells, CD8 T cells, or Tregs
Numerous studies are under way to identify synergistic combinations of checkpoint inhibitors with chemotherapy, radiotherapy, targeted therapy, or other immunotherapy strategies [2]
Summary
Immunotherapy based on checkpoint inhibitors has emerged as a potent tool for the treatment of lung cancer, the leading cause of cancer-related death worldwide. Among the numerous immunotherapeutic strategies, monoclonal antibodies that inhibit the interaction between programmed death-1 (PD-1) and its ligands have shown the most compelling clinical results in lung cancer. Monoclonal antibodies raised against PD-1 have been approved by the FDA for patients with metastatic non–small cell lung cancer [1]. By blocking PD-1, these drugs remove the inhibition of T-cell activation and restore antitumor immune responses. PD-1 inhibition is not capable of reversing all resistance mechanisms, and a proportion of patients do not respond adequately to anti–PD-1 immunotherapies. Combination therapies, which block more than one immunomodulatory pathway, have been proposed to further enhance the antitumor efficacy of anti–PD-1 individual treatments [2]
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