Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer

Abstract

In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. Importantly, the mechanisms that facilitate such infiltration or a subsequent immune suppression are not fully understood. Hence, in this study, we aimed to delineate disparate molecular pathways which MDSC utilize in murine models of colon or breast cancer. Using pathways enrichment analysis, we completed interactome maps of multiple signaling pathways in CD11b+/Gr1(high/low) MDSC from spleens and tumor infiltrates of mice with c26GM colon cancer and tumor infiltrates of MDSC in 4T1 breast cancer. In both cancer models, infiltrating MDSC, but not CD11b+ splenic cells, have been found to be enriched in multiple signaling molecules suggestive of their enhanced proliferative and invasive phenotypes. The interactome data has been subsequently used to reconstruct a previously unexplored regulation of MDSC cell cycle by the c-myc transcription factor which was predicted by the analysis. Thus, this study represents a first interactome mapping of distinct multiple molecular pathways whereby MDSC sustain cancer progression.

Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes

“…The mechanism underlying MDSC-induced L-selectin modulation closely parallels in vitro observations for an ADAM17 and ADAM10-independent ecto-protease during constitutive or inducible L-selectin shedding (i.e., triggered by antibody cross-linking of L-selectin and TcR) that is unaffected by mutation of the ADAM17 cleavage site, ADAM17/ADAM10 inhibitors, or ADAM17-deficiency (Stoddart et al, 1996; Jasuja and Mier, 2000; Walcheck et al, 2003; Li et al, 2006). Of note, tumor-induced MDSC are enriched for multiple ecto-proteases including ADAM28, ADAM9, collagenase-3 (MMP13), stromelysin (MMP3), macrophage elastase, and leukocyte elastase (Aliper et al, 2014). Moreover, at least one of these proteins, recombinant stromelysin (MMP3), can function in trans to cleave lymphocyte L-selectin in vitro (Preece et al, 1996).…”

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

“…The canonical Wnt pathway has been shown to antagonize MDSC differentiation and support the differentiation of mature DCs (66,67). A recent pathway analysis comparing MDSCs, both in the periphery and at the tumor site, with normal immature myeloid cells has provided a comprehensive look at the number of factors enriched in MDSCs in different physiological settings (68). It represents the first step toward a comprehensive understanding of how MDSC function is controlled.…”

Gemcitabine nanoparticles promote antitumor immunity against melanoma

“…58 In LCP-GMP group, the downregulation of p -STAT3 in tumors suppresses MDSCs and many pro-tumor genes such as survivin, Bcl-xL and c-Myc, leading to decreased tumor cell survival and proliferation. 23 c-Myc selectively regulates tumor-infiltrating MDSCs, 59 and c-Myc suppression correlated with the reduction of PD-L1 in tumors. 39 Further, the MDSC depletion and reversal of immunosuppression correlate with increased adaptive antitumor immune responses and mproved therapeutic outcome of melanoma.…”