NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment.

Deborah Reynaud,Roland Abi Nahed,Vincent Sapin,Wael Traboulsi,Padma Murthi,Houssine Boufettal,Mohamed Benharouga,Frederic Sergent,Nadia Alfaidy,Odile Filhol,Touria Aboussaouira,Christophe Battail,Pierre-Adrien Bolze,Nicolas Lemaitre,Pascale Hoffmann,Rima Slim

doi:10.3390/cancers13122999

Abstract

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

Highlights

NLRP7 is a member of the NOD-like receptors (NLR), a family of proteins that plays a crucial role in the innate immune response
We previously showed that NLRP7 is highly expressed in the human placenta and that its levels are elevated during the first trimester of pregnancy [25]
We found that NLRP7 protein was predominantly localized to the syncytiotrophoblast layer and was highest in CC followed by complete hydatidiform moles (CHM) and normal placenta, Figure 1A,B

Summary

Introduction

NLRP7 is a member of the NOD-like receptors (NLR), a family of proteins that plays a crucial role in the innate immune response. The inflammasome is defined as an intracellular multimeric protein complex that contains a sensor receptor (NLR) [3], an adaptor protein called ASC [3,4], and an effector enzyme, caspase-1. This complex catalyzes a cellular reaction that leads to the processing and maturation of two proinflammatory cytokines, the interleukin (IL)-1β and IL-18 [3,5]. CHM develops when one or two spermatozoa fertilize an oocyte that either does not contain a nucleus or loses it after fertilization, while PHM results from dispermic fertilization of a nucleated oocyte [14,15]. CC is an invasive cancer that may spread throughout the body with the most common sites of metastases being the lungs [22], liver, and brain [20,21]

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Discussion

Conclusion