Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced Natural Killer cell activity

Clara Vigneron; Adrien Mirouse; Hamid Merdji; Christophe Rousseau; Clément Cousin; Fanny Alby-Laurent; Jean-Paul Mira; Jean-Daniel Chiche; Jean-François Llitjos; Frédéric Pène

doi:10.1080/2162402X.2019.1641391

Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced Natural Killer cell activity

Oncoimmunology. 2019 Jul 19;8(11):e1641391. doi: 10.1080/2162402X.2019.1641391. eCollection 2019.

Authors

Clara Vigneron^{1

2}, Adrien Mirouse^{1

2}, Hamid Merdji^{1

2}, Christophe Rousseau^{1

2}, Clément Cousin^{1

2}, Fanny Alby-Laurent^{1

2}, Jean-Paul Mira^{1

2

3}, Jean-Daniel Chiche^{1

2

3}, Jean-François Llitjos^{1

2

3}, Frédéric Pène^{1

2

3}

Affiliations

¹ Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.
² Université Paris Descartes, Paris, France.
³ Médecine Intensive & Réanimation, hôpital Cochin, Hôpitaux Universitaires Paris Centre, Assistance Publique - Hôpitaux de Paris, Paris, France.

Abstract

Sepsis-induced immune dysfunctions are likely to impact on malignant tumor growth. Sequential sepsis-then-cancer models of tumor transplantation in mice recovering from sepsis have shown that the post-septic immunosuppressive environment was able to promote tumor growth. We herein addressed the impact of sepsis on pre-established malignancy in a reverse cancer-then sepsis experimental model. Mice previously inoculated with MCA205 fibrosarcoma cells were subjected to septic challenges by polymicrobial peritonitis induced by cecal ligation and puncture or endotoxinic shock. The anti-tumoral immune response was assessed through the distribution of tumor-infiltrating immune cells, as well as the functions of cytotoxic cells. As compared to sham surgery, polymicrobial sepsis dampened malignant tumor growth in wild-type (WT) mice, but neither in Toll-like receptor 4 (Tlr4)^-/- nor in Myd88^-/- mice. Similar tumor growth inhibition was observed following a LPS challenge in WT mice, suggesting a regulatory role of Tlr4 in this setting. The low expression of MHC class 1 onto MCA205 cells suggested the involvement of Natural Killer (NK) cells in sepsis-induced tumor inhibition. Septic insults applied to mice with cancer promoted the main anti-tumoral NK functions of IFNγ production and degranulation. The anti-tumoral properties of NK cells obtained from septic mice were exacerbated when cultured with MHC1^low MCA205 or YAC-1 cells. These results suggest that sepsis may harbor dual effects on tumor growth depending on the sequential experimental model. When applied in mice with cancer, sepsis prevents tumor growth in a Tlr4-dependent manner by enhancing the anti-tumoral functions of NK cells.

Keywords: Natural Killer; Sepsis; Toll-like receptor 4; cancer.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by a grant from the French Intensive Care Society (Société de Réanimation de Langue Française). C. Vigneron was a recipient of a research fellowship by the Fondation ARC (Association pour la Recherche sur le Cancer). A. Mirouse was a recipient of a research fellowship “année recherche AP-HP” by the Assistance Publique - Hôpitaux de Paris.