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•Colorectal cancer patients present increased level of all MDSCs populations in peripheral blood.•Eosinophilic MDSCs can be distinguished among PMN-MDSCs in the blood of colorectal cancer patients.•In patients with colorectal cancer Mo-MDSCs correlate negatively with tumor antigen associated CD8+ T cells.•In colorectal cancer patients an increase of circulating Mo-MDSCs after surgery may be associated with a higher risk of disease recurrence during a 5-year period.

Myelotoxic injury in the bone marrow (BM) as a consequence of total body irradiation (TBI) or granulocyte colony-stimulating factor (G-CSF) mobilization results in the deposition of iC3b on BM stroma (stroma-iC3b). In the present study, we have examined how stroma-iC3b interacts with hematopoietic progenitor cells (HPCs) and the role of complement (C) and complement receptor 3 (CR3) in BM injury/repair. We demonstrate here that stroma-iC3b tethers HPCs via the inserted (I) domain of HPC complement receptor 3 (CR3, CD11b/CD18, Mac-1). Following irradiation, stroma-iC3b was observed in the presence of purified IgM and normal mouse serum (NMS), but not serum from Rag-2-/- mice, implicating a role for antibody (Ab) and the classic pathway of C activation. Furthermore, a novel role for soluble yeast β-glucan, a ligand for the CR3 lectin-like domain (LLD), in the priming of CR3+ HPC is suggested. Soluble yeast β-glucan could enhance the proliferation of tethered HPCs, promote leukocyte recovery following sublethal irradiation, and increase the survival of lethally irradiated animals following allogeneic HPC transplantation in a CR3-dependent manner. Taken together, these observations suggest a novel role for C, CR3, and β-glucan in the restoration of hematopoiesis following injury. (Blood. 2006;107:835-840)

The mechanisms regulating the homing/mobilization of hematopoietic stem/progenitor cells (HSPCs) are not fully understood. In our previous studies we showed that the complement C3 activation peptide, C3a, sensitizes responses of HSPCs to stromal-derived factor 1 (SDF-1). In this study, mobilization was induced with granulocyte colony-stimulating factor (G-CSF) in both C3-deficient (C3–/–) and C3a receptor–deficient (C3aR–/–) mice as well as in wild-type (wt) mice in the presence or absence of a C3aR antagonist, SB 290157. The data indicated (1) significantly increased G-CSF–induced mobilization in C3–/– and C3aR–/– mice compared with wt mice, (2) significantly accelerated and enhanced G-CSF–induced mobilization in wt, but not in C3–/– or C3aR–/–, mice treated with SB 290157, and (3) deposition of C3b/iC3b fragments onto the viable bone marrow (BM) cells of G-CSF–treated animals. Furthermore, mobilization studies performed in chimeric mice revealed that wt mice reconstituted with C3aR–/– BM cells, but not C3aR–/– mice reconstituted with wt BM cells, are more sensitive to G-CSF–induced mobilization, suggesting that C3aR deficiency on graft-derived cells is responsible for this increased mobilization. Hence we suggest that C3 is activated in mobilized BM into C3a and C3b, and that the C3a-C3aR axis plays an important and novel role in retention of HSPCs (by counteracting mobilization) by increasing their responsiveness to SDF-1, the concentration of which is reduced in BM during mobilization. The C3a-C3aR axis may prevent an uncontrolled release of HSPCs into peripheral blood. These data further suggest that the C3aR antagonist SB 290157 could be developed as a drug to mobilize HSPCs for transplantation.

The mechanisms regulating the homing/mobilization of hematopoietic stem/progenitor cells (HSPCs) are not fully understood. In our previous studies we showed that the complement C3 activation peptide, C3a, sensitizes responses of HSPCs to stromal-derived factor 1 (SDF-1). In this study, mobilization was induced with granulocyte colony-stimulating factor (G-CSF) in both C3-deficient (C3–/–) and C3a receptor–deficient (C3aR–/–) mice as well as in wild-type (wt) mice in the presence or absence of a C3aR antagonist, SB 290157. The data indicated (1) significantly increased G-CSF–induced mobilization in C3–/–and C3aR–/–mice compared with wt mice, (2) significantly accelerated and enhanced G-CSF–induced mobilization in wt, but not in C3–/–or C3aR–/–, mice treated with SB 290157, and (3) deposition of C3b/iC3b fragments onto the viable bone marrow (BM) cells of G-CSF–treated animals. Furthermore, mobilization studies performed in chimeric mice revealed that wt mice reconstituted with C3aR–/–BM cells, but not C3aR–/–mice reconstituted with wt BM cells, are more sensitive to G-CSF–induced mobilization, suggesting that C3aR deficiency on graft-derived cells is responsible for this increased mobilization. Hence we suggest that C3 is activated in mobilized BM into C3a and C3b, and that the C3a-C3aR axis plays an important and novel role in retention of HSPCs (by counteracting mobilization) by increasing their responsiveness to SDF-1, the concentration of which is reduced in BM during mobilization. The C3a-C3aR axis may prevent an uncontrolled release of HSPCs into peripheral blood. These data further suggest that the C3aR antagonist SB 290157 could be developed as a drug to mobilize HSPCs for transplantation.

Recently we demonstrated that complement (C) is activated in bone marrow (BM) during conditioning for transplantation and hematopoietic stem/progenitor cells (HSPC) express on their surface the C3a receptor (C3aR) and in the presence of the third C component - C3 cleavage fragments (C3a and desArgC3a) respond more robustly to a chemotactic gradient of stromal-derived factor (SDF)-1 (Reca et al., Blood2003, 101, 3784). The molecular explanation for this phenomenon is a C3a mediated increase in the incorporation of CXCR4 into membrane lipid rafts what enables CXCR4 to interact better with small GTPases from the Rho/Rac family (Wysoczynski et al. Blood2005, 105, 40–48). To elucidate this phenomenon better and to learn more on the role of the C3a-C3aR axis in homing/engraftment of HSPC we studied i) engraftment of murine HSPC derived from C3aR-deficient mice into wild type littermates and ii) human HSPC on which C3aR was blocked by C3aR antagonist SB290157 into NOD/SCID mice. We noticed that wt mice transplanted with C3aR−/ − HSPC engrafted significantly worse compared to normal littermates. Accordingly, transplantation of the same numbers of Sca-1+ cells from C3aR−/ − mice into wt littermates as compared to transplantation of wt cells resulted in i) delay by ~5–7 days in recovery of platelets and leukocytes, ii) decrease in day 12 CFU-S, and iii) decrease in the number of CFU-GM progenitors detectable in the BM cavities at day 16 after transplantation. Similarly in parallel experiments, human CD34+ cells exposed to nontoxic doses of C3aR antagonist SB29007 engrafted worse in NOD/SCID mice (p<0.0001). Next, we studied the different steps of homing of HSPC and noticed that sensitization of cells to an SDF-1 chemotactic gradient was compensated in C3aR−/ − mice probably by the activation of another putative receptor for C3a, however, the C3aR was indispensable for optimal adhesion of HSPC to endothelium and SDF-1-dependent MMP-9 secretion. In conclusion, activation of the C cascade in BM during conditioning for transplantation exposes a natural neoantigen which is recognized by immunoglobulins activating C by the classical pathway. As a consequence, C3 cleavage product, C3a, activates the C3aR on transplanted HSPC increasing the SDF-1 mediated homing of these cells.

Recently we demonstrated that complement (C) is activated in bone marrow (BM) during conditioning for transplantation and hematopoietic stem/progenitor cells (HSPC) express on their surface the C3a receptor (C3aR) and in the presence of the third C component - C3 cleavage fragments (C3a and desArgC3a) respond more robustly to a chemotactic gradient of stromal-derived factor (SDF)-1 (Reca et al., Blood 2003, 101, 3784). The molecular explanation for this phenomenon is a C3a mediated increase in the incorporation of CXCR4 into membrane lipid rafts what enables CXCR4 to interact better with small GTPases from the Rho/Rac family (Wysoczynski et al. Blood 2005, 105, 40–48). To elucidate this phenomenon better and to learn more on the role of the C3a-C3aR axis in homing/engraftment of HSPC we studied i) engraftment of murine HSPC derived from C3aR-deficient mice into wild type littermates and ii) human HSPC on which C3aR was blocked by C3aR antagonist SB290157into NOD/SCID mice. We noticed that wt mice transplanted with C3aR−/ −HSPC engrafted significantly worse compared to normal littermates. Accordingly, transplantation of the same numbers of Sca-1+ cells from C3aR−/ −mice into wt littermates as compared to transplantation of wt cells resulted in i) delay by ~5–7 days in recovery of platelets and leukocytes, ii) decrease in day 12 CFU-S, and iii) decrease in the number of CFU-GM progenitors detectable in the BM cavities at day 16 after transplantation. Similarly in parallel experiments, human CD34+cells exposed to nontoxic doses of C3aR antagonist SB29007 engrafted worse in NOD/SCID mice (p<0.0001). Next, we studied the different steps of homing of HSPC and noticed that sensitization of cells to an SDF-1 chemotactic gradient was compensated in C3aR−/ −mice probably by the activation of another putative receptor for C3a, however, the C3aR was indispensable for optimal adhesion of HSPC to endothelium and SDF-1-dependent MMP-9 secretion. In conclusion, activation of the C cascade in BM during conditioning for transplantation exposes a natural neoantigen which is recognized by immunoglobulins activating C by the classical pathway. As a consequence, C3 cleavage product, C3a, activates the C3aR on transplanted HSPC increasing the SDF-1 mediated homing of these cells.