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

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:

• Sepsis
• cancer
• Toll-like receptor 4
• Natural Killer

Acknowledgments

We are indebted to Matthieu Benard at the animal facility and to Patrice Vallin at the cytometry and immunobiology (CYBIO) facility of the Cochin Institute.

Authors’ contributions

F Pène designed the study.

C Vigneron, A Mirouse, H Merdji, C Rousseau, C Cousin and F Alby-Laurent performed the research.

C Vigneron and F Pène drafted the manuscript.

C Vigneron, A Mirouse, H Merdji, C Rousseau, C Cousin, F Alby-Laurent, JP Mira, JD Chiche, JF Llitjos and F Pène analysed and interpreted the data, and contributed to writing the manuscript.

Availability of data and material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Consent for publication

Not applicable

Disclosure of potential conflicts of interest

The authors declare that they have no competing interests

Ethics approval

The study was approved by the Paris Descartes University ethics committee for animal experimentation, Paris, France (#12-094 & #17-054)

Meeting presentation

Presented in part at the 45th and 46th Congresses of the Société de Réanimation de Langue Française, Paris, France.

Supplemantary material

Supplemental data for this article can be access on the publisher’s website.

Additional information

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.