The growing diversity and spectrum of actionof myeloid-derived suppressor cells

Alberto Mantovani

Istituto Clinico Humanitas IRCCS, University of Milan, Rozzano, Milan, Italy

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of myelo-

monocytic cells endowed with suppressive activity. MDSC expand and acquire suppres-

sive functions in chronic inflammatory conditions, in particular in neoplastic disorders. As

exemplified in two reports in this issue of the European Journal of Immunology, progress has

been made in defining MDSC-inducing signals, MDSC phenotypic diversity and spectrum

of action. These recent results provide a basis to better define the relationship of MDSC

with the adaptive immune responses of mononuclear phagocytes and neutrophils and to

exploit their function in a therapeutic setting.

Key words: Macrophages . Myeloid-derived suppressor cells . Neutrophils

See accompanying articles by Elkabets et al. and Hegde et al.

Cells belonging to the myelomonocytic differentiation pathway

have long been known to have immunoregulatory activity, a

concept that has seen a renaissance in recent years with the

characterization of myeloid-derived suppressor cells (MDSC)

[1–5]. The MDSC definition is operational in nature and these

suppressor cells are a heterogeneous population. MDSC expand

and acquire suppressive activity under chronic inflammatory

conditions such as cancer and infection. Two reports in this issue

of the European Journal of Immunology expand the diversity and

spectrum of MDSC action as well as the signals involved in

inducing these cells [6, 7].

MDSC are members of the myelomonocytic differentiation

pathway; these cells expand/mobilize in the presence of tumors

and under chronic infections/inflammatory conditions. Progress

has been made in defining signals and molecular pathways that

can sustain MDSC expansion and differentiation in vitro or

in vivo. In particular, it has been recently shown that the c/EBPbtranscription factor plays a key role in the generation of in vitro

bone marrow-derived and in vivo tumor-induced MDSC [8].

Moreover, STAT3 promotes MDSC differentiation and expansion

and IRF8 has been suggested to counterbalance MDSC-inducing

signals [9, 10]. These results shed fresh new light on the genetic

orchestrators of MDSC expansion, differentiation and function

and in principle provide tools to test their role with rigorous

genetic approaches (Fig. 1), a critical evidence that is currently

missing.

Cytokines are key signals involved in the generation of

MDSC. Tumor cell lines overexpressing colony stimulating

factors (e.g. G-CSF and GM-CSF) have long been used in

in vivo models of MDSC generation. GM-CSF, G-CSF and IL-6

allow the in vitro generation of MDSC that retain their suppres-

sive function in vivo [8]. In addition to CSF, other cytokines such

as IL-6, IL-10, VEGF, PGE2 and IL-1 have been implicated in the

development and regulation of MDSC [11–19]. The current

finding by Elkabets et al., that IL-1 is involved in promoting

MDSC generation [7], is relevant to the central role of IL-1

and its regulation in cancer-related inflammation [20, 21].

Moreover the key role of IL-1 brings us back to the roots

of this pleiotropic cytokine, which was also identified as haemo-

poietin-1 [22]. Macrophage-CSF has been shown to be essential

for the generation of tumor infiltrating CD11b1Gr11myeloid cells

[23]. This finding, together with the analysis of cells actually

mediating suppression [24], strongly suggests that a major

component of the suppressive function of MDSC is accounted for

by cells belonging to the mononuclear phagocyte differentiation

pathway.Correspondence: Prof. Alberto Mantovanie-mail: alberto.mantovani@humanitasresearch.it

& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

Eur. J. Immunol. 2010. 40: 3317–3320 DOI 10.1002/eji.201041170 HIGHLIGHTS 3317C

om

men

tary

The MDSC population is markedly diverse including imma-

ture myeloid elements, monocyte-like cells, and cells belonging to

the granulocyte differentiation pathway. In many settings,

monocyte-like cells account for the suppressive activity [4, 24];

however, granulocyte-like MDSC can also be responsible for the

suppressive activity, such as that reported in human renal cell

carcinoma [25]. Interestingly, recent results have shown that

neutrophils are endowed with previously unsuspected plasticity

[26, 27] and tumor-associated neutrophils can undergo polar-

ization and mediate inhibition of adaptive responses [28]. Thus,

diversity is a hallmark of myelomonocytic cells endowed with

suppressive activity in the blood, in lymphoid tissues (see current

study by Hegde et al. [6]) and in tumors [1, 29].

MDSC activity was originally described as suppressors of

T cells, in particular of CD81 T-cell responses [2, 4, 5]. As shown

by Elkabets et al. [7], the spectrum of action of MDSC activity

also encompasses NK cells [7, 30, 31], dendritic cells and

macrophages [4]. Seemingly conflicting results reporting oppo-

site effects of MDSC on NK cells [30, 32] will need to be resolved.

The finding of differential interaction of NK cells with polarized

macrophages [33] may provide a basis for the seemingly different

observations.

In addition to host-derived factors, pharmacologic agents also

have profound impact on MDSC. Chemotherapeutic agents

belonging to different classes have been reported to inhibit

MDSC [34–38]. Although this effect may well be secondary

to inhibition of hematopoietic progenitors, there may be grounds

for search of selectivity based on long-known differential effects

of these agents on immunocompetent cells and macrophages

[39]. The report by Hegde et al. [6] shows that cannabinoid

receptor agonists elicit an induction of MDSC. This provocative

finding has obvious implications for the recreational use of

cannabinoids. In addition, it raises the possibility of utilizing

cannabinoids to obtain MDSC for immunosuppressive cell ther-

apy. It will be important to asses the actual relevance of this

finding in humans.

The rapidly accumulating new information has shed new light

on molecular pathways and diversity of MDSC. As usual, new

evidence raises new questions or revisits old questions. It remains

to be elucidated to what extent the MDSC activity can actually be

attributed to a monocyte or neutrophil subset(s) or state of

activation [40]. Genetic evidence is needed that MDSC indeed

play a role in primary carcinogenesis. Finally, translation to the

bedside of better understanding of myelomonocytic function

remains the ultimate challenge.

Acknowledgements: This work was supported by Associazione

Italiana per la Ricerca sul Cancro, Ministero della Salute. and

European Commission.

Conflict of interest: The author declares no financial or

commercial conflict of interest.

References

1 Biswas, S. K. and Mantovani, A., Macrophage plasticity and interaction

with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 2010. 11:

889–896.

2 Gabrilovich, D. I. and Nagaraj, S., Myeloid-derived suppressor cells as

regulators of the immune system. Nat. Rev. Immunol. 2009. 9: 162–174.

Blood lymphoid organs Tissue (cancer)

G-CSFMonocyte

Cannabinoids

GM-CSF

M-CSFTAMCCL2

+

Cancer/Infection IL-10

PGE2

MDSC

S100A9

+ –

IL-6

IL-1Suppression

TANStat3CEBP/β

IRF8PMN

–

Chemotherapy

MØCD8 NK

Figure 1. MDSC diversity and regulation. MDSC are operationally defined as a heterogeneous population of myelomonocytic cells endowed withsuppressive function. They regulate the function of T cells, NK cells and macrophages.

Eur. J. Immunol. 2010. 40: 3317–3320Alberto Mantovani3318

& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

3 Bronte, V., Myeloid-derived suppressor cells in inflammation: uncovering

cell subsets with enhanced immunosuppressive functions. Eur.

J. Immunol. 2009. 39: 2670–2672.

4 Sinha, P., Clements, V. K., Bunt, S. K., Albelda, S. M. and Ostrand-

Rosenberg, S., Cross-talk between myeloid-derived suppressor cells and

macrophages subverts tumor immunity toward a type 2 response.

J. Immunol. 2007. 179: 977–983.

5 Sica, A. and Bronte, V., Altered macrophage differentiation and

immune dysfunction in tumor development. J. Clin. Invest. 2007. 117:

1155–1166.

6 Hegde, V. L., Nagarkatti, M. and Nagarkatti, P. S., Cannabinoid receptor

activation leads to massive mobilization of myeloid-derived suppressor

cells with potent immunosuppressive properties. Eur. J. Immunol. 2010. 40:

3358–3371.

7 Elkabets, M., Ribeiro, V. S. G., Dinarello, C. A., Ostrand-Rosemberg, S.,

Di Santo, J. P., Apte, R. N. and Vosshenrich, C. A. J., IL-1beta regulates a

novel myeloid-derived suppressor cell subset that impairs NK cell

development and function. Eur. J. Immunol. 2010. 40: 3347–3357.

8 Marigo, I., Bosio, E., Solito, S., Mesa, C., Fernandez, A., Dolcetti, L., Ugel,

S. et al., Tumor-induced tolerance and immune suppression depend on

the C/EBPbeta transcription factor. Immunity 2010. 32: 790–802.

9 Stewart, T. J., Liewehr, D. J., Steinberg, S. M., Greeneltch, K. M. and

Abrams, S. I., Modulating the expression of IFN regulatory factor 8 alters

the protumorigenic behavior of CD11b1Gr-11 myeloid cells. J. Immunol.

2009. 183: 117–128.

10 Kujawski, M., Kortylewski, M., Lee, H., Herrmann, A., Kay, H. and Yu, H.,

Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice.

J. Clin. Invest. 2008. 118: 3367–3377.

11 Apolloni, E., Bronte, V., Mazzoni, A., Serafini, P., Cabrelle, A., Segal, D. M.,

Young, H. A. and Zanovello, P., Immortalized myeloid suppressor cells

trigger apoptosis in antigen-activated T lymphocytes. J. Immunol. 2000.

165: 6723–6730.

12 Gabrilovich, D., Ishida, T., Oyama, T., Ran, S., Kravtsov, V., Nadaf, S. and

Carbone, D. P., Vascular endothelial growth factor inhibits the develop-

ment of dendritic cells and dramatically affects the differentiation of

multiple hematopoietic lineages in vivo. Blood 1998. 92: 4150–4166.

13 Ochoa, A. C., Zea, A. H., Hernandez, C. and Rodriguez, P. C., Arginase,

prostaglandins, and myeloid-derived suppressor cells in renal cell

carcinoma. Clin. Cancer Res. 2007. 13: 721s–726s.

14 Sinha, P., Clements, V. K., Fulton, A. M. and Ostrand-Rosenberg, S.,

Prostaglandin E2 promotes tumor progression by inducing myeloid-

derived suppressor cells. Cancer Res. 2007. 67: 4507–4513.

15 Song, X., Krelin, Y., Dvorkin, T., Bjorkdahl, O., Segal, S., Dinarello, C. A.,

Voronov, E., and Apte, R. N., CD11b1/Gr-11 immature myeloid cells

mediate suppression of T cells in mice bearing tumors of IL-1beta-

secreting cells. J. Immunol. 2005. 175: 8200–8208.

16 Bunt, S. K., Yang, L., Sinha, P., Clements, V. K., Leips, J. and Ostrand-

Rosenberg, S., Reduced inflammation in the tumor microenvironment

delays the accumulation of myeloid-derived suppressor cells and limits

tumor progression. Cancer Res. 2007. 67: 10019–10026.

17 Marrache, F., Tu, S. P., Bhagat, G., Pendyala, S., Osterreicher, C. H.,

Gordon, S., Ramanathan, V. et al., Overexpression of interleukin-1beta in

the murine pancreas results in chronic pancreatitis. Gastroenterology 2008.

135: 1277–1287.

18 Tu, S., Bhagat, G., Cui, G., Takaishi, S., Kurt-Jones, E. A., Rickman, B., Betz,

K. S. et al., Overexpression of interleukin-1beta induces gastric inflam-

mation and cancer and mobilizes myeloid-derived suppressor cells in

mice. Cancer Cell 2008. 14: 408–419.

19 Zhang, Y., Liu, Q., Zhang, M., Yu, Y., Liu, X. and Cao, X., Fas signal

promotes lung cancer growth by recruiting myeloid-derived suppressor

cells via cancer cell-derived PGE2. J. Immunol. 2009. 182: 3801–3808.

20 Mantovani, A., Allavena, P., Sica, A. and Balkwill, F., Cancer-related

inflammation. Nature 2008. 454: 436–444.

21 Garlanda, C., Anders, H. J. and Mantovani, A., TIR8/SIGIRR: an IL-1R/TLR

family member with regulatory functions in inflammation and T cell

polarization. Trends Immunol. 2009. 30: 439–446.

22 Dinarello, C. A., Immunological and inflammatory functions of the

interleukin-1 family. Annu. Rev. Immunol. 2009. 27: 519–550.

23 Priceman, S. J., Sung, J. L., Shaposhnik, Z., Burton, J. B., Torres-Collado,

A. X., Moughon, D. L., Johnson, M. et al., Targeting distinct tumor-

infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor

evasion of antiangiogenic therapy. Blood 2010. 115: 1461–1471.

24 Movahedi, K., Guilliams, M., Van den Bossche, J., Van den Bergh, R.,

Gysemans, C., Beschin, A., De Baetselier, P. and Van Ginderachter, J. A.,

Identification of discrete tumor-induced myeloid-derived suppressor cell

subpopulations with distinct T cell-suppressive activity. Blood 2008. 111:

4233–4244.

25 Rodriguez, P. C., Ernstoff, M. S., Hernandez, C., Atkins, M., Zabaleta, J.,

Sierra, R. and Ochoa, A. C., Arginase I-producing myeloid-derived

suppressor cells in renal cell carcinoma are a subpopulation of activated

granulocytes. Cancer Res. 2009. 69: 1553–1560.

26 Yang, C.-W., Strong, B. S. I., Miller, M. J. and Unanue, E. R., Neutrophils

influence the level of antigen presentation during the immune response

to protein antigens in adjuvants. J. Immunol. 2010. 185: 2927–2934.

27 Cassatella, M. A., Locati, M. and Mantovani, A., Never underestimate the

power of a neutrophil. Immunity 2009. 31: 698–700.

28 Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., Worthen,

G. S. and Alberlda, S. M., Polarization of tumor-associated neutrophil

(TAN) phenotype by TGF-beta: ‘‘N1’’ versus ‘‘N2’’ TAN – a new paradigm?

Cancer Cell 2009 16: 183–194.

29 Movahedi, K., Laoui, D., Gysemans, C., Baeten, M., Stange, G., Van den

Bossche, J., Mack, M. et al., Different tumor microenvironments contain

functionally distinct subsets of macrophages derived from Ly6C(high)

monocytes. Cancer Res. 2010. 70: 5728–5739.

30 Li, H., Han, Y., Guo, Q., Zhang, M. and Cao, X., Cancer-expanded myeloid-

derived suppressor cells induce anergy of NK cells through membrane-

bound TGF-beta 1. J. Immunol. 2009. 182: 240–249.

31 Greifenberg, V., Ribechini, E., Rossner, S. and Lutz, M. B., Myeloid-derived

suppressor cell activation by combined LPS and IFN-gamma treatment

impairs DC development. Eur. J. Immunol. 2009. 39: 2865–2876.

32 Nausch, N., Galani, I. E., Schlecker, E. and Cerwenka, A., Mononuclear

myeloid-derived ‘‘suppressor’’ cells express RAE-1 and activate natural

killer cells. Blood 2008. 112: 4080–4089.

33 Bellora, F., Castriconi, R., Dondero, A., Reggiardo, G., Moretta, L.,

Mantovani, A., Moretta, A. and Bottino, C., Human natural killer

cells and unpolarized or polarized macrophages: molecular interac-

tions and differences in functional outcome. Proc. Natl. Sci. USA 2010. In

press.

34 Kodumudi, K. N., Woan, K., Gilvary, D. L., Sahakian, E., Wei, S. and Djeu,

J. Y., A novel chemoimmunomodulating property of docetaxel: suppres-

sion of myeloid-derived suppressor cells in tumor bearers. Clin. Cancer

Res. 2010. 16: 4583–4594.

35 Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R. and Albelda, S. M.,

Gemcitabine selectively eliminates splenic Gr-11/CD11b1 myeloid

suppressor cells in tumor-bearing animals and enhances antitumor

immune activity. Clin. Cancer Res. 2005. 11: 6713–6721.

Eur. J. Immunol. 2010. 40: 3317–3320 HIGHLIGHTS 3319

& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

36 Le, H. K., Graham, L., Cha, E., Morales, J. K., Manjili, M. H. and Bear, H. D.,

Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c

mice bearing 4T1 mammary carcinoma and augments expansion of

T cells from tumor-bearing mice. Int. Immunopharmacol. 2009. 9: 900–909.

37 Ko, J. S., Zea, A. H., Rini, B. I., Ireland, J. L., Elson, P., Cohen, P., Golshayan,

A. et al., Sunitinib mediates reversal of myeloid-derived suppressor cell

accumulation in renal cell carcinoma patients. Clin. Cancer Res. 2009. 15:

2148–2157.

38 Ko, J. S., Rayman, P., Ireland, J., Swaidani, S., Li, G., Bunting, K. D., Rini, B.

et al., Direct and differential suppression of myeloid-derived suppressor

cell subsets by sunitinib is compartmentally constrained. Cancer Res.

2010. 70: 3526–3536.

39 Mantovani, A., Polentarutti, N., Luini, W., Peri, G. and Spreafico, F., Role of

host defense mechanisms in the antitumor activity of adriamycin and

daunomycin in mice. J. Natl. Cancer Inst. 1979. 63: 61–66.

40 Mantovani, A., From phagocyte diversity and activation to probiotics:

back to Metchnikoff. Eur. J. Immunol. 2008. 38: 3269–3273.

Abbreviation: MDSC: myeloid-derived suppressor cells

Full correspondence: Prof. Alberto Mantovani, Istituto Clinico

Humanitas IRCCS, University of Milan, Via Manzoni 56, 20089 Rozzano,

Milan, Italy

Fax: 139-02-8224-5101

e-mail: alberto.mantovani@humanitasresearch.it

See accompanying articles:

http://dx.doi.org/10.1002/eji.201040667

http://dx.doi.org/10.1002/eji.201041037

Received: 15/10/2010

Accepted: 18/10/2010

Eur. J. Immunol. 2010. 40: 3317–3320Alberto Mantovani3320

& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu