Pluto Bioinformatics

GSE146211: Activation of a collaborative innate-adaptive immune response suppresses metastatic breast and ovarian cancer in mice

Bulk RNA sequencing

Many cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells, preventing immune control of the cancer. However, macrophages polarized by lipopolysaccharide (a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFN) instead kill cancer cells. They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages might therefore be a strategy for controlling tumors. Here, we show that monophosphoryl lipid A (MPLA, a TLR4 agonist used as a vaccine adjuvant)- and IFN-activated human macrophages from metastatic breast cancers to kill the same patients cancer cells in vitro. Excitingly, intratumoral injection of MPLA with IFN not only controlled local tumor growth but also led to reduced metastasis in mouse models of metastatic luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA and IFN reprogrammed peritoneal macrophages and suppressed metastasis in ID8-p53-/- ovarian tumor-bearing mice. We found that the combination of MPLA and IFN reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, reprogramming tumor-associated (CD206+) macrophages to tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted IL12 and TNF. Both macrophages and T cells, including memory T cells (CD44+CD62L-), were critical for the anti-metastatic effects of MPLA and IFN. MPLA and IFN are used individually in humans, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing. SOURCE: Bodu Liu (liuleopold@gmail.com) - Sun Yat-sen University