Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells

Lu Wang,Lin Xie,Bin Xie,Dan Hu

doi:10.1007/s10637-022-01218-6

Abstract

SummaryBackground. In cancer, myeloid-derived suppressor cells (MDSCs) are known to escape the host immune system by developing a highly suppressive environment. However, little is known about the molecular mechanism behind MDSC-mediated tumor cell evasion of the immune system. Toll-like receptor (TLR) signaling elicited in the tumor microenvironment has the potential to induce MDSC differentiations in different organs. Therefore, MDSC elimination by blocking the action of myeloid differentiation factor 88 (MyD88), which is a key adaptor-signaling molecule that affects TLR activity, seems to be an ideal tumor immunotherapy. Previous studies have proven that blocking MyD88 signaling with a novel MyD88 inhibitor (TJ-M2010-5, synthesized by Zhou’s group) completely prevented colitis-associated colorectal cancer (CAC) development in mice. Methods. In the present study, we investigated the impact of the novel MyD88 inhibitor on the number, phenotype, and function of MDSC in the mice model of CAC. Results. We showed that CAC growth inhibition was involved in diminished MDSC generation, expansion, and suppressive function and that MDSC-mediated immune escape was dependent on MyD88 signaling pathway activation. MyD88 inhibitor treatment decreased the accumulation of CD11b+Gr1+ MDSCs in mice with CAC, thereby reducing cytokine (GM-CSF, G-CSF, IL-1β, IL-6 and TGF-β) secretion associated with MDSC accumulation, and reducing the expression of molecules (iNOS, Arg-1 and IDO) associated with the suppressive capacity of MDSCs. In addition, MyD88 inhibitor treatment reduced the differentiation of MDSCs from myeloid cells and the suppressive capacity of MDSCs on the proliferation of activated CD4+ T cells in vitro. Conclusion. MDSCs are primary cellular targets of a novel MyD88 inhibitor during CAC development. Our findings prove that MyD88 signaling is involved in the regulation of the immunosuppressive functions of MDSCs. The novel MyD88 inhibitor TJ-M2010-5 is a new and effective agent that modulates MyD88 signaling to overcome MDSC suppressive functions, enabling the development of successful antitumor immunotherapy.

Highlights

As tumors may escape the host immune system by developing a highly suppressive environment, an increasing number of studies have focused on tumor immune evasion [1]
We investigated the impact of the novel myeloid differentiation factor 88 (MyD88) inhibitor on the number, phenotype, and function of myeloid-derived suppressor cells (MDSCs) in mice with CAC
The concentrations of granulocyte macrophage-colony stimulating factor (GM-CSF), IFN-γ, IL-1β, IL-6, and TGF-β1 in the supernatant were analyzed by ELISA according to the ELISA kit manufacturer’s instructions

Summary

Introduction

As tumors may escape the host immune system by developing a highly suppressive environment, an increasing number of studies have focused on tumor immune evasion [1]. An increased count of MDSCs has been found in the peripheral blood (PB), bone marrow (BM), lymph nodes, and tumor sites of patients and experimental animals with tumors. MDSCs have been confirmed to suppress host antitumor immunity and promote tumor progression [5,6,7]. Eliminating MDSCs may be an ideal tumor immunotherapy strategy [8, 9]. The key point of these strategies is to either decrease the number of expanding MDSCs or to attenuate their immunosuppressive activity in tumor-bearing host

Methods

Results

Discussion

Conclusion