Salmonella-mediated tumor regression involves targeting of tumor myeloid suppressor cells causing a shift to M1-like phenotype and reduction in suppressive capacity

Abstract

The effectiveness of attenuated Salmonella in inhibiting tumor growth has been demonstrated in many therapeutic models, but the precise mechanisms remain incompletely understood. In this study, we show that the anti-tumor capacity of Salmonella depends on a functional MyD88-TLR pathway and is independent of adaptive immune responses. Since myeloid suppressor cells play a critical role in tumor growth, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics, and functional activation in spleen and tumor tissue of B16.F1 melanoma-bearing mice. Salmonella treatment led to increased accumulation of splenic and intratumoral CD11b(+)Gr-1(+) myeloid cells, exhibiting significantly increased expression of various activation markers such as MHC class II, costimulatory molecules, and Sca-1/Ly6A proteins. Gene expression analysis showed that Salmonella treatment induced expression of iNOS, arginase-1 (ARG1), and IFN-γ in the spleen, but down-regulated IL-4 and TGF-β. Within the tumor, expression of iNOS, IFN-γ, and S100A9 was markedly increased, but ARG1, IL-4, TGF-β, and VEGF were inhibited. Functionally, splenic CD11b(+) cells maintained their suppressive capacity following Salmonella treatment, but intratumoral myeloid cells had significantly reduced suppressive capacity. Our findings demonstrate that administration of attenuated Salmonella leads to phenotypic and functional maturation of intratumoral myeloid cells making them less suppressive and hence enhancing the host's anti-tumor immune response. Modalities that inhibit myeloid suppressor cells may be useful adjuncts in cancer immunotherapy.

Salmonella as an Innovative Therapeutic Antitumor Agent

“…Salmonella -induced tumor inhibition occurs with alterations in myeloid cells consistent with maturation to macrophage effectors and a reduction in their suppressive capacity. The antitumor effectiveness of Salmonella relies on the induction of the innate immune response through the toll-like receptor-myeloid differentiation primary response gene ( TLR-MYD88 ) signaling pathway [14]. This is consistent with our previous report demonstrating that Salmonella induce cytokine production and antitumor activities via TLR4 signaling, which may help clarify the molecular mechanism of Salmonella -induced host antitumor responses [15].…”

Ratio of Intratumoral Macrophage Phenotypes Is a Prognostic Factor in Epithelioid Malignant Pleural Mesothelioma

“…Second, a definitive M1 macrophage marker would enhance the findings of our manuscript for this would give a true insight in the M1/M2 macrophage ratio. NOS2 expression has proven be a useful marker for M1 macrophages in several tumor types [31]–[33]. However, for mesothelioma, Soini et al and others [34], [35] have demonstrated that NOS2 is highly expressed in healthy pleura as well as in cancerous mesothelioma tissues and mesothelioma cell lines.…”

Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer

“…Total RNA was extracted from a second biopsy of each patient using the TRIzol reagent protocol (Invitrogen) and repurified on Qiagen columns (RNeasy Plus Mini kit, Qiagen) as previously described (44). Similarly, total RNA was extracted from MCF-7 and MDA-MB-231 human breast cancer cell lines.…”