Anti-tumoral Effects of Recombinant Lactococcus lactis Strain Secreting IL-17A Cytokine.

Elsa Jacouton,Isabelle Naas,Nicolas Pouderous,Vasco Azevedo,Philippe Langella,Florian Chain,Ana Paula Pessoa Vilela,Anne-Sophie Boucard,Edgar Torres Maravilla,Luis G Bermúdez-Humarán

doi:10.3389/fmicb.2018.03355

Abstract

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine produced by TH17 cells that participates and contributes in host defense and autoimmune disease. We have recently reported antitumor properties of the probiotic strain of Lactobacillus casei BL23 in mice and TH17 cells was shown to play an important role in this beneficial effect. In order to better understand the role of IL-17A in cancer, we constructed a recombinant strain of Lactococcus lactis producing this cytokine and we determined its biological activity in: (i) a bioassay test for the induction of IL-6 production by murine fibroblasts 3T3 L1 cells line and (ii) in a mouse allograft model of human papilloma virus (HPV)-induced cancer. Our data show that recombinant L. lactis produces and efficiently secretes biologically active IL-17A cytokine. Interestingly, ∼26% of mice intranasally treated with L. lactis-IL-17A and challenged with TC-1 cells remained tumor free over the experiment, in contrast to control mice treated with the wild type strain of L. lactis which developed 100% of aggressive tumors. In addition, the median size of the ∼74% tumor-bearing mice treated with recombinant L. lactis-IL-17A, was significantly lower than mice treated with L. lactis-wt. Altogether, our results demonstrate that intranasal administration with L. lactis secreting IL-17A results in a partial protection against TC-1-induced tumors in mice, confirming antitumor effects of this cytokine in our cancer model.

Highlights

Cancer remains a serious health concern in human society worldwide and colorectal cancer (CRC), prostrate, lung, stomach, liver and breast cancers are among the major types associated with significant mortality every year (Ferlay et al, 2012)
Recent studies described the role of specific members of microbiota in cancer therapy by targeting the immune checkpoint blockade (CTLA-4, PD-1) (Sivan et al, 2015; Vetizou et al, 2015; Gopalakrishnan et al, 2018; Routy et al, 2018)
In one of our two CRC models (Lenoir et al, 2016), the anti-tumor effects of L. casei BL23 were associated with the reduction of pro-inflammatory cytokines, but the precise molecular and cellular mechanisms involved in tumor prevention of this bacterium remain unclear

Summary

Introduction

Cancer remains a serious health concern in human society worldwide and colorectal cancer (CRC), prostrate, lung, stomach, liver and breast cancers are among the major types associated with significant mortality every year (Ferlay et al, 2012). Despite the great number of studies that have demonstrated anticancer effects of different strains of Lactobacillus (Khazaie et al, 2012; Konishi et al, 2016; Lenoir et al, 2016), the precise host molecular mechanisms of these antitumor properties remain unclear. Generation probiotics, such as Akkermansia muciniphila and Faecalibacterium genus as well as genetically modified microorganisms (GMOs) (O’Toole et al, 2017) have demonstrated beneficial effects in the context of cancer, promoting the immune checkpoints inhibitors therapy targeting the programmed cell death protein 1 (PD-1) and cytotoxic lymphocyte-associated antigen (CTLA-4). Other studies support the role of Bifidobacterium, Bacteroides, Faecalibacterium and Akkermansia species in cancer therapy targeting the immune checkpoint blockade (CTLA-4, PD-1), showing a T cellspecific anti-tumor-induced response (Sivan et al, 2015; Vetizou et al, 2015; Gopalakrishnan et al, 2018; Routy et al, 2018)

Methods

Results

Conclusion