Dados do Resumo

Título

Effects of the complement system on the expression of immune checkpoint co-receptors in lung cancer

Introdução

With high mortality rates, lung cancer affects millions of people worldwide, highlighting the need for new treatments such as immune checkpoint blockade (ICB). While ICB is effective, especially for non-small cell lung cancer (NSCLC), some patients do not respond. The complement system (CS) influences both innate and adaptive immune responses and is associated with increased inflammation. Although its action in the tumor microenvironment is known, its precise role is still under investigation.

Objetivo

We aim to evaluate the role of the complement system in modulating immune checkpoint coreceptors in NSCLC. This research allows us to know whether CS components can influence the response to immunotherapy, allowing new approaches for improving responses to ICB.

Métodos

We performed an analysis of public databases, evaluating the expression of complement system components (C2, C3, C4, and C5) and receptors (C5aR1/2 and C3aR) in samples from patients with lung squamous cell carcinoma (LUSC). Additionally, we assessed the correlation between immune checkpoint coreceptors (PD-L1, PD-L2, GAL9 and HVEM) and the CS in these patients. In vitro, we analyzed the gene expressions of CS components and receptors in three NSCLC cell lines (H1975, A549, and H1299) and evaluated their expression in response to pro-inflammatory stimuli such as IFNg. Given that C5aR1/2 was expressed in these cell lines, we investigated whether its ligand, C5a, either alone or in combination with IFNg, could influence the expression of immune checkpoint coreceptors at the gene and/or protein level in these cell lines.

Resultados

Initially, analyses using databases revealed the presence of CS components and their receptors in LUSC samples. This finding was confirmed in vitro with NSCLC cell lines, except for two genes: C3, which was not expressed in the H1299 cell line, and C3aR, which was not expressed in the A549 cell line. We observed that inflammatory stimulation with IFNg increased the expression of C2 and C4 in the cell lines. However, no change in the expression of CS receptors was observed following the same stimulation. Database analysis showed correlations between C3aR and PD-L2, C3aR and HVEM, and C5aR1 and HVEM in tumor tissue. Given that IFNg can alter the expression of ICB coreceptors, we observed an increase in the expression of PD-L1, PD-L2, HVEM, and GAL9, in vitro. We also noted that combined treatment with IFNg and C5a led to a decrease in the gene expression of these coreceptors, suggesting an antitumor effect of C5a. This result was also observed in the H1975 cell line using flow cytometry.

Conclusões

From this work, we can conclude that CS is expressed in LUSC samples as well as in NSCLC cell lines and that C5a appears to influence the expression of ICB coreceptors in an inflammatory environment. Additionally, in lung cancer patients, we observed a correlation between C3aR and PD-L2; C3aR and HVEM; and C5aR1 and HVEM, suggesting a possible interaction between CS and ICB coreceptors, which opens new perspectives for the development of innovative therapies.

Financiador do resumo

CAPES – Financing Code 001

Palavras Chave

immunotherapy; Complement System; Lung Neoplasms