Complement C1s and C4d as Prognostic Biomarkers in Renal Cancer: Emergence of Noncanonical Functions of C1s.

Marie V Daugan,Victoria Poillerat,Margot Revel,Virginie Verkarre,Xavier Cathelineau,Isabelle Cremer,Jules Russick,Diane Damotte,Christine Gaboriaud,Guillaume Lacroix,Pierre Validire,Lubka T Roumenina,Marie-Agnès Dragon-Durey,Wolf H Fridman,Tania Robe-Rybkine,Maxime Meylan,Rafael Sánchez-Salas ,Antoine Bougouïn ,Catheriné Sautès-Fridman ,Véronique Fremeaux‐Bacchi ,Géraldine Perkins ,Yann Vano ,Stéphane Oudard ,Arnaud Méjean ,Anne Grünenwald

doi:10.1158/2326-6066.cir-20-0532

Abstract

The complement system plays a complex role in cancer. In clear cell renal cell carcinoma (ccRCC), local production of complement proteins drives tumor progression, but the mechanisms by which they do this are poorly understood. We found that complement activation, as reflected by high plasma C4d or as C4d deposits at the tumor site, was associated with poor prognosis in two cohorts of patients with ccRCC. High expression of the C4-activating enzyme C1s by tumor cells was associated with poor prognosis in three cohorts. Multivariate Cox analysis revealed that the prognostic value of C1s was independent from complement deposits, suggesting the possibility of complement cascade-unrelated, protumoral functions for C1s. Silencing of C1s in cancer cell lines resulted in decreased proliferation and viability of the cells and in increased activation of T cells in in vitro cocultures. Tumors expressing high levels of C1s showed high infiltration of macrophages and T cells. Modification of the tumor cell phenotype and T-cell activation were independent of extracellular C1s levels, suggesting that C1s was acting in an intracellular, noncanonical manner. In conclusion, our data point to C1s playing a dual role in promoting ccRCC progression by triggering complement activation and by modulating the tumor cell phenotype and tumor microenvironment in a complement cascade-independent, noncanonical manner. Overexpression of C1s by tumor cells could be a new escape mechanism to promote tumor progression.See related Spotlight by Magrini and Garlanda, p. 855. See article by Daugan et al., p. 909 (40).

Highlights

The complement system is a first line of immune defence against pathogens [1]
We describe a complement-rich phenotype for clear cell renal cell carcinoma (ccRCC) in which overexpression of C1s confers a poor prognosis in early stage disease
C1q originates from macrophages, the remaining proteins are produced by tumor cells

Summary

Introduction

The complement system is a first line of immune defence against pathogens [1]. In cancer, the complement system plays a context-dependent role, either killing tumor cells or generating local chronic inflammation, thereby promoting tumor growth [2]. As measured by deposits of C4 activation fragments in tumor sections, is associated with a poor prognosis in non-small cell lung cancer (NSCLC) [9] and ccRCC [8], suggesting a canonical complement cascade–related mechanism. Mouse fibroblasts, which do not produce C1s and do not form tumors when injected in vivo, gain tumorigenic capacity when transfected with the C1s gene [13] This tumorigenic potential is dependent on the enzymatic activity of C1s [14]. The pro-tumoral effect of C1s was found to involve three major mechanisms: 1) a canonical function of cleaving C4 and initiating the classical pathway; 2) a function that includes non-canonical, intracellular activity that directly affects the tumor cell transcriptome, phenotype and capacity to 3) activate T cells. C1s can promote tumor cell proliferation and escape from immunosurveillance through modulation of the tumor microenvironment

Methods

Results

Conclusion