Pro-Resolving Factor Administration Limits Cancer Progression by Enhancing Immune Response Against Cancer Cells

Abstract

Cancers are consequences of cellular dysfunction leading to an aberrant cellular multiplication and proliferation, subsequently yielding metastasis formation. Inflammatory reaction, with immune cell recruitment, is the main defense against precancerous lesions. However, an inflammatory environment also favors cancer cell progression, with cancer cell evasion from immune surveillance, leading to cancer development. Current therapeutic strategies enhance this natural immune response in order to restore immunosurveillance. The variety of these strategies is a predominant source of inflammatory mediators used by cancer cells to grow, differentiate, and migrate, therefore encouraging metastasis formation. For this reason, during cancer progression, limiting inflammation appears to be an innovative strategy to avoid the escape of cancer cells and potentially enhance the efficacy of antitumor therapies. Thus, this study aims to investigate the impact of administering pro-resolving factors (SuperMApo® drug candidate), which are inducers of inflammation resolution, in the framework of cancer treatment. We have observed that administering pro-resolving mediators issued from apoptotic cell efferocytosis by macrophages controlled peritoneal cancer progression by limiting cancer cell dissemination to the blood and mesenteric lymph nodes. This observation has been linked to an increase of macrophage mobilization in both peritoneal cavity and mesenteric lymph nodes. This control is associated to a restricted immunosuppressive myeloid cell circulation and to an IFN-γ-specific anti-tumor T-cell response. Altogether, these results suggest that administering proresolving factors could provide a new additional therapeutic alternative to control cancer progression.

Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation

“…Resolution therapy has been proposed to be used in cancer ( 127 ), which belongs also to chronic inflammatory diseases associated with non-resolving inflammation ( 1 ). We observed that SuperMApo reduces tumor cell dissemination to the blood and mesenteric lymph nodes ( 105 ). Moreover, SuperMApo increases specific anti-tumor T cell responses.…”

“…Moreover, SuperMApo increases specific anti-tumor T cell responses. This increase of specific anti-tumor IFN-g responses induced by the administration of SuperMApo was found correlated to the induction of macrophages highly expressing MHC class II molecules (105). The transcriptomic analysis of different macrophage subsets identified that mouse pro-resolving macrophages are enriched for genes coding for antigen processing and presentation (MHC class II genes [H2-Aa]) in comparison with naive macrophages (36).…”

“…The SuperMApo drug candidate consists of the secretome of macrophages co-cultured with apoptotic cells at a ratio of 1:5 for 48 hours ( 100 , 104 , 105 ). In this setting, apoptotic cells are totally eliminated in 24 hours.…”

“…In this setting, apoptotic cells are totally eliminated in 24 hours. SuperMApo has been generated using human and mouse cells, and tested in different xenogeneic and mouse models of acute and chronic inflammation ( 100 , 104 , 105 ). Mouse SuperMApo is generated using thioglycollate-elicited mouse macrophages co-cultured with mouse apoptotic thymocytes (rendered apoptotic by a 35 Gray-irradiation), whereas M2 (M-CSF-treated) monocyte-derived human macrophages cultured with human apoptotic lymphocytes allow us to generate human SuperMApo ( 100 ).…”

“…Concerning experimental models of chronic diseases associated with non-resolving inflammation, SuperMApo has been tested in the mouse model of RA, CIA ( 100 ), as well as in different models of IBD, including dextran sodium sulfate (DSS)-induced and naive T cell transfer-induced colitis ( 104 ), as well as DSS-induced xenogeneic colitis ( 100 ). The capacity to reduce chronic inflammation has also been evaluated in the setting of cancer ( 105 ). SuperMApo has also been tested in xenogeneic graft- versus -host disease (GvHD) ( 100 ), and a biopsy forceps-wounded colonic mucosa model ( 104 ).…”