Tumor cells hijack macrophage-produced complement C1q to promote tumor growth

Lubka Roumenina (1, 2, 3) , Marie V Daugan (1, 2, 3) , Remi Noe (1, 2, 3) , Florent Petitprez (1, 2, 3, 4) , Yann A Vano (1, 2, 3, 5) , Rafael Sanchez-Salas (6) , Etienne Becht (1, 2, 3) , Julie Meilleroux (1, 2, 7) , Bénédicte Le Clec'H (1, 2) , Nicolas A Giraldo (8, 1, 2, 3) , Nicolas Merle (1, 2, 3) , Cheng-Ming Sun (1, 2, 3) , Virginie Verkarre (1, 2, 5) , Pierre Validire (9) , Janick Selves (7) , Laetitia Lacroix (1, 2, 3) , Olivier Delfour (10) , Isabelle Vandenberghe (10) , Celine Thuilliez (10) , Sonia Keddani (1, 2, 3) , Imene B Sakhi (1, 3) , Eric Barret (6) , Pierre J. Ferré (10) , Nathalie Corvaïa (10) , Alexandre Passioukov (10) , Eric Chetaille (10) , Marina Botto (11) , Aurélien de Reynies (4) , Stephane Marie Oudard (12) , Arnaud Mejean (1, 2, 5) , Xavier Cathelineau (6, 1, 2) , Catherine Sautès-Fridman (1, 2, 3) , Wolf Hervé Fridman (1, 2, 3)

1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
2 USPC - Université Sorbonne Paris Cité
3 SU - Sorbonne Université
4 Ligue Nationale Contre le Cancer - Paris
5 HEGP - Hôpital Européen Georges Pompidou [APHP]
6 Service d'urologie [Institut Mutualiste Montsouris]
7 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
8 Johns Hopkins University School of Medicine [Baltimore]
9 IMM - Institut Mutualiste de Montsouris
10 Centre de R&D Pierre Fabre - Centre de Recherche Pierre Fabre
11 Imperial College London
12 Service d'oncologie médicale [CHU HEGP]

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts (n = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.

Domaines: Cancer; Immunité innée; Urologie et Néphrologie

Lubka Roumenina, Marie V Daugan, Remi Noe, Florent Petitprez, Yann A Vano, et al.. Tumor cells hijack macrophage-produced complement C1q to promote tumor growth. Cancer Immunology Research, 2019, 7 (7), pp.1091-1105. ⟨10.1158/2326-6066.CIR-18-0891⟩. ⟨hal-02285096⟩