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

01-jul-2017 | Revista: Cancer Discovery

Daniel Ajona 1 2 3 4 , Sergio Ortiz-Espinosa 1 4 , Haritz Moreno 1 2 , Teresa Lozano 2 5 , María J Pajares 1 2 3 6 , Jackeline Agorreta 1 2 3 6 , Cristina Bértolo 1 , Juan J Lasarte 2 5 , Silvestre Vicent 1 2 6 , Kai Hoehlig 7 , Axel Vater 7 , Fernando Lecanda 1 2 3 6 , Luis M Montuenga 1 2 3 6 , Ruben Pio 8 2 3 4

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.

CITA DEL ARTÍCULO Cancer Discov. 2017 Jul;7(7):694-703. doi: 10.1158/2159-8290.CD-16-1184. Epub 2017 Mar 13

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