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T-Cell–Secreted Tnfa Induces Emergency Myelopoiesis and Myeloid-Derived Suppressor Cell Differentiation in Cancer Mohamad F

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T-Cell–Secreted Tnfa Induces Emergency Myelopoiesis and Myeloid-Derived Suppressor Cell Differentiation in Cancer Mohamad F Published OnlineFirst November 2, 2018; DOI: 10.1158/0008-5472.CAN-17-3026 Cancer Tumor Biology and Immunology Research T-cell–Secreted TNFa Induces Emergency Myelopoiesis and Myeloid-Derived Suppressor Cell Differentiation in Cancer Mohamad F. Al Sayed1,2, Michael A. Amrein1,2, Elias D. Buhrer€ 1,2, Anne-Laure Huguenin1,2, Ramin Radpour1,2, Carsten Riether1,2, and Adrian F. Ochsenbein1,2 Abstract Hematopoiesis in patients with cancer is characterized by reduced production of red blood cells and an Bone marrow TNFα increase in myelopoiesis, which contributes to the Tumor HSCs CD4+ T cells immunosuppressive environment in cancer. Some TNFα tumors produce growth factors that directly stimulate MPP1s/MPP2s CD8+ T cells myelopoiesis such as G-CSF or GM-CSF. However, for a majority of tumors that do not directly secrete Circulation hematopoietic growth factors, the mechanisms CMPs/GMPs Emergency myelopoiesis involved in the activation of myelopoiesis are poorly characterized. In this study, we document in different TNFα murine tumor models activated hematopoiesis with increased proliferation of long-term and short- MDSCs term hematopoietic stem cells and myeloid progen- itor cells. As a consequence, the frequency of myeloid- a + + þ TNF secreted by CD4 (and partially CD8 ) T cells induces myelopoiesis, increasing the derivedsuppressorcellsanditsratiotoCD8 Tcells production of MDSCs, which inhibit the CD8+ T-cell immune response in the tumor. increased in tumor-bearing mice. Activation of hema- © 2018 American Association for Cancer Research topoiesis and myeloid differentiation in tumor-bear- ing mice was induced by TNFa, which was mainly þ secreted by activated CD4 T cells. Therefore, the activated adaptive immune system in cancer induces emergency myelopoiesis and immunosuppression. Significance: These findings characterize a regulatory circuit linking activated T cells to suppression of tumor-specific immune responses, providing a conceptual advance in the understanding of emergency-hematopoiesis in cancer and opening new targets for therapeutic approaches. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/2/346/F1.large.jpg. Introduction is perturbed and characterized by a preferential myeloid dif- ferentiation at the expense of erythroid and lymphoid differ- Steady-state hematopoiesis in the bone marrow is a tightly entiation (2). This leads to the accumulation of immature and controlled and regulated process that ensures the continuous immunosuppressive myeloid cells, primarily myeloid-derived generation of all blood lineages (1). In cancer, hematopoiesis suppressorcells(MDSC;refs.3,4).Inmice,MDSCsexpress þ þ granulocytic (CD11b Ly6G Ly6Clo;Gr-MDSC)ormonocytic þ þ markers (CD11b Ly6C Ly6Glo;M-MDSCs;ref.5).Theysup- 1 Tumor Immunology, Department of BioMedical Research, University of Bern, press the adaptive immune response to cancer and promote Switzerland. 2Department of Medical Oncology, Inselspital, Bern University tumor growth by promoting tumor cell survival, angiogenesis, Hospital, University of Bern, Switzerland. and metastasis (4, 5). MDSCs are short-lived and have to be Note: Supplementary data for this article are available at Cancer Research continuously replenished from hematopoietic stem and pro- Online (http://cancerres.aacrjournals.org/). genitor cells (HSPC) in the bone marrow and with subsequent M.F. Al Sayed and M.A. Amrein contributed equally to this article. mobilization and acquisition of immunosuppressive activity Corresponding Author: Adrian F. Ochsenbein, Department of Medical Oncol- in the tumor microenvironment (5). Although the mechanisms ogy, Inselspital, Bern University Hospital and University of Bern, Bern 3010, are not yet fully understood, the accumulation of MDSCs and Switzerland. Phone: 41-31-632-41-14; Fax: 41-632-41-19; E-mail: the aberrant myelopoiesis in patients with cancer are attributed [email protected] to the secretion of tumor-derived factors. Hematopoietic cyto- doi: 10.1158/0008-5472.CAN-17-3026 kines such as GM-CSF, G-CSF, IL6, and IL1 are produced in a Ó2018 American Association for Cancer Research. variety of human tumors such as brain, colorectal, and lung 346 Cancer Res; 79(2) January 15, 2019 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst November 2, 2018; DOI: 10.1158/0008-5472.CAN-17-3026 T-cell–Secreted TNFa Activates Myelopoiesis in Cancer cancer and regulate the production of MDSCs from bone (control: sunflower oil). For tumor induction in KP transgenic marrow progenitors (6–8). In the MMTV-PgMT breast cancer mice, an adenoviral vector expressing Cre recombinase was mouse model, G-CSF released by mammary tumor cells intratracheallyinjectedinto6-week-oldKPmice(16). induced hematopoietic stem cell (HSC) expansion and granu- lopoiesis in the bone marrow to replenish short-living Cell lines MDSCs (7, 9). Similarly, it has been documented that tumor MC57 fibrosarcoma, B16F10 melanoma, MC38 colon ade- growth in Lewis lung carcinoma model is accompanied nocarcinoma, and mouse Lewis lung carcinoma 3LL cell lines with an increase in peripheral myeloid cells and lineage were a gift from Prof. Rolf Zinkernagel, Institute of Experimen- À þ þ (Lin) c-kit sca-1 stem and progenitor cells (LSK). This was tal Immunology, University of Zurich (Zurich, Switzerland) attributed to insulin-like growth factor-I receptor signaling and have been characterized and described before (15, 17). in HSCs (10). Furthermore, GM-CSF has been shown to induce No additional authentication was performed. Cell cultures were the differentiation of granulocyte monocyte myeloid progeni- regularly tested for Mycoplasma contamination. tors (GMP) at the expense of lymphoid and erythroid progeni- tors (11). Similarly, GM-CSF–secreted by mammary 4T1 Bone marrow lineage depletion tumors led to the expansion of myeloid progenitors and accu- Bone marrow lineage depletion was performed by magnetic- þ þ mulation of CD11b GR-1 myeloid cells (12). In addition, activated cell sorting (MACS) negative selection using biotiny- TNFa has been shown to lead to the accumulation of MDSCs in lated Abs against red blood cell precursors (a-Ter119), B cells murine and human tumors (13, 14). (a-CD19), T cells (a-CD3e), and myeloid cells (a-Gr1), MACS Importantly, the vast majority of solid tumors do not secrete streptavidin beads, and LS columns (Miltenyi Biotec). Negative hematopoietic cytokines (8). The mechanisms underlying the cell fraction was used for analysis or further cell sorting. modulation of myelopoiesis in these tumors are poorly under- stood. In this study, we document an activated hematopoiesis Antibodies and flow cytometry with increased numbers of long-term (LT) and short-term (ST) Anti-mouse mAbs against the following antigens were HSCs and myeloid progenitor cells in transplanted, chemically used for flow cytometry: CD4 (GK1.5), CD8 (53-6.7), CD3e induced, and spontaneous murine tumor models. This led to an (145-2C11), CD19 (6D5), CD11b (M170), Ly6C (HK1.4), accumulation of immunosuppressive MDSCs in tumor-bearing Ly6G (1A8), Gr1 (Ly6C/G; RB6-8C5), c-Kit (2B8), CD34 mice. Interestingly, TNFa secreted by T cells induced prolifer- (RAM34), CD16/32 (FcgR; 93), IL-7Ra (CD127; A7R34), ation of HSPCs, myeloid differentiation, and the accumulation CD90.1 (Ox-7), CD90.2 (30-H12), CD48 (HM48-1), CD135 of MDSCs. Therefore, the activated adaptive immune system (A2F10), CD150 (TC15-12F12.2), CD45 (30-F11); Sca-1 in cancer induces immunosuppressive myeloid cells that damp- (D7), CD45.1 (A20), CD45.2 (104), and BrdU and isotype en the tumor-specific immune response. (BD Pharmingen). Cells were washed in PBS and resuspended in the corresponding FACS antibodies for 30 minutes at 4C. Cells were then washed in PBS and analyzed on a LSRII (BD Materials and Methods Biosciences). Alternatively, cells of interest were FACS sorted Mice by FACS Aria II (BD Biosciences). Data were analyzed with À À À À À À À À C57BL/6 (BL/6), Rag-1 / (Rag / ), IFNg-R / , TNFR1/2 / , FlowJo software (Treestar). and Ly5.1 mice were from the Institute of Laboratory Animal À À Science (Zurich, Switzerland). IL6 / mice were obtained from M. Blood analysis Kopf (Swiss Federal Institute of Technology, Zurich, Switzerland). Blood was collected into EDTA-coated tubes and white blood Ubi-GFP mice were from C. Muller€ (Institute of Pathology, Uni- cell counts were determined using a Vet ABC animal blood LSL-G12D/WT Fl/Fl versity of Bern, Bern, Switzerland). K-ras ; p53 (KP) counter (Medical Solution GmbH) and/or by FACS staining. mice were kindly provided by Alfred Zippelius (Tumor Immu- nology, University of Basel, Basel, Switzerland). All animals Isolation of tumor-infiltrating lymphocytes were on BL/6 background. All animal experiments were per- Tumors were cut into very small pieces by a scalpel, digested formed in 6- to 8-week-old mice, housed in a specific pathogen- for one hour at 37C in PBS supplemented with 1 mg/mL free facility. All animal experiments were approved by the Collagenase-IA, 100 mg/mL Hyaluronidase-V (Sigma), 40 U/mL fi Veterinary Of ce of the Canton Bern and performed according DNase-I (Roche), 5 mmol/L CaCl2, and 5 mmol/L MgCl2, washed toSwisslawsforanimalprotection. and filtered to get a single-cell suspension. Tumor-infiltrating þ lymphocytes (TIL) were isolated by positive MACS of CD45 Tumor models cells using biotinylated anti-CD45, MACS streptavidin beads, MC57, MC38, B16F10, and 3LL tumors were induced as and LS columns (Miltenyi
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