A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and Metastasis

• Published in: Cancer discovery Vol. 7; no. 7; p. 694
• Main Authors: Ajona, Daniel, Ortiz-Espinosa, Sergio, Moreno, Haritz, Lozano, Teresa, Pajares, María J, Agorreta, Jackeline, Bértolo, Cristina, Lasarte, Juan J, Vicent, Silvestre, Hoehlig, Kai, Vater, Axel, Lecanda, Fernando, Montuenga, Luis M, Pio, Ruben
• Format: Journal Article
• Language: English
• Published: United States 01-07-2017
• Subjects: Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Aptamers, Peptide - immunology; Aptamers, Peptide - therapeutic use; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation - drug effects; Complement C5a - antagonists & inhibitors; Complement C5a - immunology; Drug Synergism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Neoplasm Metastasis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Signal Transduction
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.cd-16-1184

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.
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.
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