Nlrp7 Promotes Choriocarcinoma Growth And Progression Through The Establishment Of An Immunosuppressive Microenvironment

Simple Summary NLRP7 is the major gene responsible for recurrent hydatidiform mole (HM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). Among women with one HM (sporadic HM), about 1-9% develop a second mole (recurrent HM). While the association of biallelic mutations in NLRP7 with recurrent HM is well established, its role in the development and the immune tolerance of CC was unknown. The present work was conducted to investigate the direct involvement of NLRP7 in the development of CC and to provide evidences of its contribution in maternal immune tolerance. The study demonstrates that NLRP7 is directly involved in CC growth and downregulates the maternal immune response, thus fostering tumor growth and dissemination. Our study proposes that an increased expression of NLRP7 plays a significant role as a facilitator of CC growth, and therefore, NLRP7 should be categorized among important actors of CC development. The clinical relevance of NLRP7 in this rare female reproductive cancer highlights its therapeutic promise as a molecular target. 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.