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Published on: May 2, 2025
A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and Metastasis
Daniel Ajona1,2,3,4, Sergio Ortiz-Espinosa1,4, Haritz Moreno1,2
1University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.
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.
Insights
Combining C5a and programmed cell death protein 1 (PD-1) blockade significantly reduces lung cancer growth and metastasis in preclinical models. This novel strategy enhances antitumor immune responses and prolongs survival, supporting clinical evaluation for lung cancer treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have revolutionized non-small cell lung cancer treatment.
- The role of the complement system, specifically C5a signaling, in modulating the tumor microenvironment remains an area of active investigation.
Purpose of the Study:
- To investigate the synergistic antitumor effects of combining C5a pathway inhibition with PD-1 blockade in lung cancer models.
- To evaluate the impact of this combination therapy on tumor growth, metastasis, immune cell infiltration, and survival.
Main Methods:
- Utilized syngeneic lung cancer models.
- Administered RMP-14 antibody to block PD-1.
- Administered an L-aptamer to inhibit C5a signaling.
- Assessed tumor growth, metastasis, CD8 T cell frequency, and myeloid-derived suppressor cell levels.
Main Results:
- Combination therapy markedly reduced tumor growth and metastasis.
- Prolonged survival was observed in treated animals.
- A negative association between CD8 T cells and myeloid-derived suppressor cells was noted, suggesting reversal of T-cell exhaustion.
Conclusions:
- Combined blockade of C5a and PD-1 exhibits synergistic antitumor activity in preclinical lung cancer models.
- This strategy enhances anti-tumor immune responses by modulating immune cell populations within the tumor microenvironment.
- The findings provide a strong preclinical rationale for evaluating anti-C5a and anti-PD-1 therapies in combination for lung cancer patients.
