SET/PP2A signaling regulates macrophage positioning in hypoxic tumor regions by amplifying chemotactic responses

다국어 초록 (Multilingual Abstract)

Tumor-associated macrophages (TAMs) are one of the main cellular components in the tumor microenvironment (TME). In many types of solid tumors, TAMs tend to accumulate in hypoxic areas and are intimately related to poor patient prognosis. However, the underlying mechanisms by which TAMs infiltrate hypoxic tumor regions remain unclear. In this study, we report that genetic deletion of SE translocation (SET) in myeloid cells inhibited the entry of TAMs into the hypoxic tumor region and abated their proangiogenic and immunosuppressive functions, ultimately inhibiting tumor growth. Mechanistically, in response to hypoxic tumor supernatant stimulation, SET in macrophages shuttled between the nucleus and cytoplasm via the PKC-CK2α signaling axis. Cytoplasmic retention of SET increased ERK and P38 signaling by inhibiting PP2A, which promoted TAM migration into the hypoxic area and polarization toward the M2 phenotype. Therefore, we conclude that SET modulates tumor immunity by acting as a key regulator of macrophage positioning and function in the tumor.

참고문헌 (Reference)

1 Fukukawa, C., "pp32/ I-1(PP2A)negatively regulates the Raf-1/MEK/ERK pathway" 226 : 155-160, 2005

2 Federico, A., "Urotensin-II receptor : a double identity receptor involved in vasoconstriction and in the development of digestive tract cancers and other tumors" 17 : 109-121, 2017

3 Boldajipour, B., "Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine" 1 : e89289-, 2016

4 Devalaraja, S., "Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression" 180 : 1098-1114, 2020

5 Jeong, H., "Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis" 79 : 795-806, 2019

6 Chanmee, T., "Tumor-associated macrophages as major players in the tumor microenvironment" 6 : 1670-1690, 2014

7 He, Z., "Tumor-associated macrophages and their functional transformation in the hypoxic tumor microenvironment" 12 : 741305-741305, 2021

8 Masucci, M. T., "Tumor associated neutrophils. their role in tumorigenesis, metastasis, prognosis and therapy" 9 : 1146-, 2019

9 Labani-Motlagh, A., "The tumor microenvironment : a milieu hindering and obstructing antitumor immune responses" 11 : 940-, 2020

10 Emami Nejad, A., "The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment" 21 : 62-, 2021

11 Henze, A. T., "The impact of hypoxia on tumor-associated macrophages" 126 : 3672-3679, 2016

12 Bikfalvi, A., "The CC and CXC chemokines: major regulators of tumor progression and the tumor microenvironment" 318 : C542-C554, 2020

13 Gong, D. P., "TGF beta signaling plays a critical role in promoting alternative macrophage activation" 13 : 31-, 2012

14 Ko, S. H., "Succinate promotes stem cell migration through the GPR91-dependent regulation of DRP1-mediated mitochondrial fission" 7 : 12582-, 2017

15 Kersten, K., "Spatiotemporal co-dependency between macrophages and exhausted CD8(+)T cells in cancer" 40 : 624-638, 2022

16 Gutiérrez, A., "Role of phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in calcium signaling pathways linked to the α1-adrenoceptor in resistance arteries" 10 : 55-, 2019

17 Jing, X., "Role of hypoxia in cancer therapy by regulating the tumor microenvironment" 18 : 157-, 2019

18 Hung, M. H., "Reprogramming the oncogenic response : SET protein as a potential therapeutic target in cancer" 21 : 685-694, 2017

19 Lee, Y. H., "Regulation of protein kinase CK2 catalytic activity by protein kinase C and phospholipase D2" 121 : 131-139, 2016

20 Resjö, S., "Protein phosphatase 2A is the main phosphatase involved in the regulation of protein kinase B in rat adipocytes" 14 : 231-238, 2002

21 Zhao, B., "PP2A regulates upstream members of the c-jun N-terminal kinase mitogen-activated protein kinase signaling pathway" 29 : 181-188, 2008

22 Zheng, H. Y., "PP2A inhibits cervical cancer cell migration by dephosphorylation of p-JNK, p-p38 and the p-ERK/MAPK signaling pathway" 38 : 115-123, 2018

23 Kiely, M., "PP2A : the wolf in sheep’s clothing?" 7 : 648-669, 2015

24 Noman, M. Z., "PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation" 211 : 781-790, 2014

25 Hata, Y., "Okadaic acid : a tool to study the hippo pathway" 11 : 896-902, 2013

26 Yin, Z., "Myeloid-derived suppressor cells : roles in the tumor microenvironment and tumor radiotherapy" 144 : 933-946, 2019

27 Cess, C. G., "Multi-scale modeling of macrophage-T cell interactions within the tumor microenvironment" 16 : e1008519-, 2020

28 Noman, M. Z., "Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response" 31 : 357-377, 2011

29 Mehla, K., "Metabolic regulation of macrophage polarization in cancer" 5 : 822-834, 2019

30 Topalian, S. L., "Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy" 16 : 275-287, 2016

31 Kessenbrock, K., "Matrix metalloproteinases : regulators of the tumor microenvironment" 141 : 52-67, 2010

32 Engelhardt, J. J., "Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells" 21 : 402-417, 2012

33 Vitale, I., "Macrophages and metabolism in the tumor microenvironment" 30 : 36-50, 2019

34 Corliss, B. A., "Macrophages : an inflammatory link between angiogenesis and lymphangiogenesis" 23 : 95-121, 2016

35 Zhou, X., "Macrophage-mediated tumor cell phagocytosis : opportunity for nanomedicine intervention" 31 : 2006220-, 2021

36 Murdoch, C., "Macrophage migration and gene expression in response to tumor hypoxia" 117 : 701-708, 2005

37 Gordon, S., "Macrophage clearance of apoptotic cells : a critical assessment" 9 : 127-, 2018

38 Rivera, L. B., "Location, location, location: macrophage positioning within tumors determines pro- or antitumor activity" 24 : 687-689, 2013

39 Casazza, A., "Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity" 24 : 695-709, 2013

40 Noman, M. Z., "Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia" 309 : C569-C579, 2015

41 Park, J. E., "Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift" 38 : 5158-5173, 2019

42 Kong, B., "Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer" 6 : 32154-32160, 2015

43 McNamee, E. N., "Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function" 55 : 58-70, 2013

44 Korbecki, J., "Hypoxia alters the expression of CC chemokines and CC chemokine receptors in a tumor—a literature review" 21 : 5647-, 2020

45 Li, X., "Hypoxia activates notch4 via ERK/JNK/P38 MAPK signaling pathways to promote lung adenocarcinoma progression and metastasis" 9 : 780121-, 2021

46 Zhang, B., "Hyperglycemia modulates M1/M2macrophage polarization via reactive oxygen species overproduction in ligatureinduced periodontitis" 56 : 991-1005, 2021

47 Ballbach, M., "Expression of checkpoint molecules on myeloid-derived suppressor cells" 192 : 1-6, 2017

48 Shang, A., "Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-β1 axis" 19 : 117-, 2020

49 Su, P., "Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages" 80 : 1438-1450, 2020

50 Guo, Y., "Effects of microvesicles on cell apoptosis under hypoxia" 2019 : 5972152-, 2019

51 Pippa, R., "Effect of FTY720 on the SET-PP2A complex in acute myeloid leukemia;SET binding drugs have antagonistic activity" 28 : 1915-1918, 2014

52 Mancino, A., "Divergent effects of hypoxia on dendritic cell functions" 112 : 3723-3734, 2008

53 Gotz, J., "Distinct role of protein phosphatase 2A subunit Calpha in the regulation of E-cadherin and beta-catenin during development" 93 : 83-93, 2000

54 Broz, M. L., "Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity" 26 : 638-652, 2014

55 Ge, Y., "Decursin promotes HIF-1αproteasomal degradation and immune responses in hypoxic tumour microenvironment" 78 : 153318-, 2020

56 Kumar, V., "Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors" 32 : 654-668, 2017

57 Mizukami, Y., "CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer" 122 : 2286-2293, 2008

58 Zhou, Y., "Blockade of the phagocytic receptor MerTK on tumor-associated macrophages enhances P2X7R-dependent STING activation by tumor-derived cGAMP" 52 : 357-373, 2020

59 Palazon, A., "An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression" 32 : 669-683, 2017

60 Mehrabi, M., "Active role of the necrotic zone in desensitization of hypoxic macrophages and regulation of CSC-fate : a hypothesis" 8 : 235-, 2018

61 Arriazu, E., "A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia" 10 : 3-, 2020

62 Bayarkhangai, B., "A comprehensive and perspective view of oncoprotein SET in cancer" 7 : 3084-3094, 2018