Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are
important regulators of immune responses in cancer and have been directly
implicated in promotion of tumor progression. However, the heterogeneity of
these cells and lack of distinct markers hampers the progress in understanding
of the biology and clinical importance of these cells. Using partial enrichment
of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC
and high density neutrophils from the same cancer patients had a distinct gene
profile. Most prominent changes were observed in the expression of genes
associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density
lipoprotein (LDL) was one of the most increased regulators and its receptor
oxidized LDL receptor 1 OLR1 was one of the most overexpressed
genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by
OLR1 was practically undetectable in neutrophils in
peripheral blood of healthy donors, whereas 5–15% of total
neutrophils in cancer patients and 15–50% of neutrophils in
tumor tissues were LOX-1+. In contrast to their
LOX-1− counterparts, LOX-1+ neutrophils had
gene signature, potent immune suppressive activity, up-regulation of ER stress,
and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER
stress in neutrophils from healthy donors up-regulated LOX-1 expression and
converted these cells to suppressive PMN-MDSC. Thus, we identified a specific
marker of human PMN-MDSC associated with ER stress and lipid metabolism, which
provides new insight to the biology and potential therapeutic targeting of these
cells.
Summary
Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that are critically important for the regulation of immune responses in cancer. They contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limits selective targeting of these cells. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSC. The main mechanism of FATP2 mediated suppressive activity involved uptake of arachidonic acid (AA) and synthesis of prostaglandin E2 (PGE2). The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to selectively inhibit the functions of PMN-MDSC and improve the effect of cancer therapy.
Summary
Tumor associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited antitumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated down-regulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this cross talk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.
In this study, using single-cell RNA-seq, cell mass spectrometry, flow cytometry, and functional analysis, we characterized the heterogeneity of polymorphonuclear neutrophils (PMNs) in cancer. We describe three populations of PMNs in tumor-bearing mice: classical PMNs, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and activated PMN-MDSCs with potent immune suppressive activity. In spleens of mice, PMN-MDSCs gradually replaced PMNs during tumor progression. Activated PMN-MDSCs were found only in tumors, where they were present at the very early stages of the disease. These populations of PMNs in mice could be separated based on the expression of CD14. In peripheral blood of cancer patients, we identified two distinct populations of PMNs with characteristics of classical PMNs and PMN-MDSCs. The gene signature of tumor PMN-MDSCs was similar to that in mouse activated PMN-MDSCs and was closely associated with negative clinical outcome in cancer patients. Thus, we provide evidence that PMN-MDSCs are a distinct population of PMNs with unique features and potential for selective targeting opportunities.
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