Abstract
One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy.
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Data availability
The microarray data are publicly available (Gene Expression Omnibus accession code GSE150465). A TCGA dataset of 640 patients with CRC is available at cBioPortal (https://www.cbioportal.org/study/summary?id=coadread_tcga). Source data are provided with this paper.
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Acknowledgements
We thank H.-F. Yang-Yen and S. Robine for providing Tctpflox mice and Villin-Cre-ERT2 mice, respectively. We also thank T. Nitta, T. Tanoue and K. Honda for providing materials. We thank M. Sugahara for technical assistance. This work was supported in part by a Grant-In-Aid for Young Scientists 18030848 (S. Hangai); Scientific Research (S) 15638461 (T.T.); Scientific Research (A) 20298458 (T.T.); and a Research Fellowship for Young Scientists 19J00887 (S. Hibino) from the Ministry of Education, Culture, Sports, Science of Japan (MEXT); Grant AMED-PRIME JP20gm6110008 (H.Y.) from the Japan Agency for Medical Research and Development; the Uehara Memorial Foundation (S. Hangai); the Takeda Science Foundation (S. Hangai); and the Naito Foundation (H.Y.). The Department of Inflammology is supported by the BONAC Corporation.
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Contributions
S. Hangai, H.Y. and T.T. designed the research; S. Hangai., Y.K., C.-Y. C., T. Kawamura and H.Y. performed experiments; S. Hangai, Y.K., C.-Y. C., S. Hibino, T. Kawamura, K.M., K.K. and H.Y. analyzed data; T. Kodama, T. Kawamura, D.Y., Y.N., R.T., M.O. and H.O. contributed new reagents or analytic tools; S. Hangai, H.Y. and T.T. gave directions for the project and wrote the paper.
Corresponding authors
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Competing interests
A patent is pending regarding this study; the patent applicant is the University of Tokyo. Inventors are T.T., H.Y. and S. Hangai. The anti-TCTP monoclonal antibody is covered in the patent application (Japanese patent application no. 2020-147222). The remaining authors declare no competing interests.
Additional information
Peer review information Nature Immunology thanks Michael Lotze and Yuting Ma for their contribution to the peer review of this work. Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data
Extended Data Fig. 1 Tumor cell death and release of immunomodulatory molecules.
a, Representative images of hematoxylin & eosin (H&E) and TUNEL staining of the SL4 tumor cells undergoing cell death in C57BL/6 mice (top row). Higher magnification images from the black boxes in the top row are displayed in the lower row. Arrowheads indicate necrotic lesions. Scale bars = 100 μm. The experiments were performed twice with similar results. b, PECs (2 × 105 cells) were incubated with the conditioned supernatant of dead SL4 cells (2 × 106 cells) for 2 hours then subjected to a microarray analysis (n = 2). A volcano plot shows differentially expressed genes indicated in red or green. Sup.: conditioned supernatant. c, PECs (2 × 105 cells) were stimulated with conditioned supernatant of dead SL4 cells (2 × 106 cells) for 2 hours then Cxcl1 (far left), Cxcl2 (near left), Tnf (near right) and Il1b (far right) mRNA were quantified by RT-qPCR (n = 3). Sup.: conditioned supernatant. n represents biologically independent samples (b, c). Data are shown as means ± standard error of the mean (s.e.m.).
Extended Data Fig. 2 Identification of the dead-cell-derived immunomodulator(s).
a, A schematic of strategy to purify immunogenic molecule(s) from the conditioned supernatant. b, Conditioned SL4 supernatant was subjected to anion (Hitrap Q) and cation (Hitrap S) exchange column chromatography. The flow-through of the Hitrap S column was collected and subjected to Hitrap Q column. The binding fraction was collected and then subjected to size-exclusion chromatography. Each fraction was added to PECs (Cxcl1, Cxcl2 and Il1b; 2 × 105 cells) or RAW264.7 cells (Tnf; 2 × 105 cells) and incubated for 2 hours. Cxcl1 (upper), Cxcl2 (upper middle), Tnf (lower middle) and Il1b (lower) mRNA were quantified by RT-qPCR. c, Fractions 25, 26 and 27, which showed cytokine-inducing activity, were subjected to SDS-PAGE and silver staining. The band (indicated by an arrow), the intensity of which correlates with the cytokine mRNA induction level, was excised and then subjected to LC-MS analysis. This analysis revealed that TCTP is the most abundant protein.
Extended Data Fig. 3 Dependence of TCTP for tumor cell growth.
a, SL4 cells were subjected to apoptosis (serum-free and adriamycin) or necrosis (freeze-and-thaw). Conditioned media were collected and TCTP protein levels were determined by immunoblotting (n = 3). b, Sera from B16F10 (left) or Meth-A (right) tumor bearing mice were collected 0 (NTB; n = 3) and 21 (TB; n = 6) days after subcutaneous tumor injection and TCTP levels were quantified by immunoblotting. NTB: non-tumor bearing. TB: tumor bearing. c, TCTP protein expression in SL4, B16F10 and Meth-A cells without (WT) or with CRISPR/Cas9-mediated Tctp gene inactivation (KO). Whole cell lysates of the indicated cell lines were prepared and subjected to immunoblot analysis for the TCTP and β-actin proteins. The experiments were performed twice with similar results. d, Cell number measurements of WT and TCTP KO SL4 cells grown in vitro at the indicated time points (n = 3). e, TCTP WT and KO SL4 cells (2 × 105 cells) were cultured under normal (20% O2, 10% FBS), low serum (20% O2, 1% FBS) or hypoxic (1% O2, 10% FBS) condition. After 72 h, cell numbers were counted (n = 3). f, WT, TCTP KO and WT-TCTP (TCTP KO cells expressing WT TCTP cDNA) SL4 cells (2 × 105 cells) were transplanted subcutaneously into C57BL/6 mice (n = 5) and tumor volumes were measured at the indicated time points. g, h, Cell number measurements of WT and TCTP KO B16F10 (g) or Meth-A cells (h) grown in vitro at the indicated time points (n = 3). n represents biologically independent samples (a, d, e, g, h) or animals (b, f). Unpaired two-sided Student’s t-test (b, e), repeated measures one-way ANOVA with Tukey’s multiple comparisons test (f). Data are shown as means ± s.e.m.
Extended Data Fig. 4 Functional effect of extracellular TCTP in the induction of chemokine mRNAs.
a, Confocal microscopy analysis of SL4 mutant cells. TCTP KO (left), WT-TCTP (TCTP KO cells expressing WT TCTP cDNA; middle), and IL-2ss-TCTP SL4 cells (TCTP cells expressing cDNA for IL-2ss-TCTP; right) were stained for TCTP and nuclei (DAPI). Scale bars = 20 μm. b, PECs (2 × 105 cells) were stimulated with conditioned media from Mock or IL-2ss-TCTP SL4 cells for 2 hours then Cxcl1 (left) and Cxcl2 (right) mRNAs measured by RT-qPCR (n = 3). c, WT and TCTP KO SL4 cells (2 × 105 cells) were transplanted subcutaneously into C57BL/6 mice (n = 5). Tumors were then excised at day 21 and whole tumor lysates were prepared. G-CSF (left) and GM-CSF (right) levels were determined by cytometric bead array (CBA). n represents biologically independent samples (b) or animals (c).Unpaired two-sided Student’s t-test (b, c). Data are shown as means ± s.e.m.
Extended Data Fig. 5 TCTP modulates MDSC number and in vivo tumor growth.
a, WT or TCTP KO B16F10 cells (1 × 105 cells) were transplanted subcutaneously into C57BL/6 mice. After 17 days, single cell suspension was prepared from the tumors and subject to flow cytometry analysis (n = 4). Shown are percentages of PMN-MDSC or M-MDSC within CD45+ cells. b, WT (n = 3) and TCTP KO (n = 4) Meth-A cells (5 × 105 cells) were transplanted into C57BL/6 mice and flow cytometry analysis was performed as in (a). Shown are percentages of PMN-MDSC or M-MDSC within CD45+ cells. c, TCTP KO SL4 cells were transplanted subcutaneously into C57BL/6 mice. At day 1, 4, 7, 10 and 13, PBS control or PMN-MDSCs isolated from spleen and bone marrow from SL4 tumor bearing mice were inoculated intraperitoneally. Tumor volume was then measured at the indicated time points. PBS; n = 5, PMN-MDSC; n = 4. d, Mock (KO) SL4 cells and IL-2ss-TCTP cells (2 × 105 cells) were each transplanted subcutaneously into C57BL/6 mice. Anti-Ly6G or control IgG was administered intraperitoneally every 2 days starting at day 1 (n = 5). (Left) Tumor volume was then measured at the indicated time points. (Right) Shown are percentages of PMN-MDSC within CD45+ cells. e, WT and TCTP KO SL4 cells (2 × 105 cells) were transplanted subcutaneously into C57BL/6 mice (n = 3). After 18 days, single cell suspension was prepared from the tumors and subject to flow cytometry analysis. Mean fluorescence intensity (MFI) of the indicated markers for NK cell activation was determined. n represents biologically independent samples animals (a-e). Unpaired two-sided Student’s t-test (a-c, e), repeated measures one-way ANOVA with Tukey’s multiple comparisons test (d). Data are shown as means ± s.e.m.
Extended Data Fig. 6 Effect of TCTP on the expression of immune checkpoint molecules and angiogenesis.
a, b, Mock and IL-2ss-TCTP SL4 cells (2 × 105 cells) were transplanted subcutaneously into C57BL/6 mice (n = 4). After 21 days, single cell suspension was prepared from the tumors and subject to flow cytometry analysis. Mean fluorescence intensity (MFI) of PD-L1 (a) and PD-1 (b) was determined. c, (Left) Representative CD31 stains of TCTP WT and KO SL4 tumor subcutaneously injected into C57BL/6 mice. The experiments were performed twice with similar results. Scale bar = 100 μm. (Right) Quantification of CD31 positive area (n = 5). n represents biologically independent animals (a-c). Unpaired two-sided Student’s t-test (c). Data are shown as means ± s.e.m.
Extended Data Fig. 7 Extracellular TCTP mediates a crosstalk between PMN-MDSCs and M-MDSCs in tumor immune microenvironment.
a, PECs (2 × 105 cells) or SL4 cells (1 × 105 cells) were stimulated with indicated concentration of a recombinant TCTP for 2 hours and then Cxcl1 mRNA quantified by RT-qPCR (n = 3). b, Cxcl1 mRNA levels in WT and TCTP KO SL4 cells were determined by RT-qPCR n = 3. c, SL4 (2 × 105 cells) cells were transplanted subcutaneously into C57BL/6 mice (n = 3) and after 21 days, single cell suspensions were prepared from the tumors. The indicated immune cell populations were sorted and the levels of Cxcr2 mRNA of each population were determined by RT-qPCR. The experiments were performed twice with similar results. n represents biologically independent samples (a, b) or animals (c). Unpaired two-sided Student’s t-test (b). repeated measures one-way ANOVA with Dunnett’s multiple comparisons test (c). Data are shown as means ± s.e.m.
Extended Data Fig. 8 Extracellular TCTP mediates chemokine induction and in vivo tumor growth via TLR2.
a, WT or TLR2 deficient peritoneal exudate cells (PECs) (2 × 105 cells) were stimulated with the indicated concentrations of recombinant IL-1α for 2 hours and Cxcl1 mRNA levels were quantified by RT-qPCR (n = 3). b, Immunoprecipitaion assay for binding of TCTP to TLR2. HEK293T cells transiently expressing TLR2-YFP together with Flag–TCTP were analyzed by immunoprecipitation with anti-GFP antibody, followed by immunoblotting with anti-Flag antibody (upper). TLR2 and TCTP were detected in whole cell lysates (bottom). The experiments were performed twice with similar results. c, A luciferase reporter construct containing multimerized NFκB binding motifs and the expression vector for the indicated proteins was transfected into HEK293T cells. After 24 h of transfection, HEK293T cells (2 × 104 cells) were seeded onto 96-well plate and stimulated with recombinant TCTP (15 nM or 50 nM) or an agonist for each TLR (Pam3CSK4 300 ng/ml, poly I:C 100 μg/ml, poly U 10 μg/ml, CpG-M 1μM). After 6 h of simulation, cell lysates were extracted and subjected to luciferase assay (n = 3). d, e, SL4 (d) or IL-2ss-TCTP cells (e) (2 × 105 cells) were transplanted subcutaneously into WT (SL4; n = 7, IL-2ss-TCTP; n = 6) or TLR2 KO mice (SL4; n = 5, IL-2ss-TCTP; n = 6). Tumor volumes were measured at the indicated time points. f, IL-2ss-TCTP SL4 cells (2 × 105 cells) were transplanted subcutaneously into C57BL/6 mice and tumor volumes were measured at the indicated time points. O-vanillin (50 mg/kg) was orally administered every two days starting from day 1 following tumor challenge (n = 6). n represents biologically independent samples (a, c) or animals (d-f). Unpaired two-sided Student’s t-test (c-f). Data are shown as means ± s.e.m.
Extended Data Fig. 9 Effect of anti-TCTP monoclonal antibody on Cxcl1 mRNA induction and the TCTP status in human colon cancer.
a, Whole cell lysates of WT or TCTP KO SL4 cells were prepared and subjected to immunoblot analysis by 55F3, a monoclonal antibody raised against human TCTP. The experiments were performed twice with similar results. b, PECs (2 × 105 cells) were stimulated with conditioned supernatant of SL4 cells with 55F3 or control IgG and after 2 hours of stimulation, Cxcl1 mRNA levels were determined by RT-qPCR. n = 3. Sup.: conditioned supernatant. c, TCTP WT or KO cells (1 × 105 cells) were transplanted subcutaneously into C57BL/6 mice. DHA (50 mg/kg) or DMSO was injected intraperitoneally every day from day 1 following tumor challenge (n = 6). d, (Left) The expression levels of TCTP in stromal area of normal colonic mucosa and colorectal cancer tissue were compared. (Right) The comparison was also performed between normal colonic crypt and tumor lesions. e, Co-expression plots of CD8A, GZMB, PRF1 or CD69 by TCTP mRNA in a TCGA colorectal cancer dataset (n = 382). Spearman correlation coefficients are shown. f, Correlation of cytolytic activity (defined as the geometric mean of GZMA and PRF1 mRNA expression) and TCTP mRNA in a TCGA colon cancer dataset (n = 382). Spearman correlation coefficients are shown. g, A graphical summary. TCTP is released by dead tumor cells and induces CXCL1/2 chemokines most notably in M-MDSCs. These chemokines in turn recruit PMN-MDSCs into the TIME, thereby suppressing anti-tumor immune responses to promote tumor growth. n represents biologically independent samples (b), animals (c) or human samples (d-f). Repeated measures one-way ANOVA with Dunnett’s multiple comparisons test (b) or Tukey’s multiple comparisons test (c), unpaired two-sided Student’s t-test (d). Data are shown as means ±s.e.m.
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The gating strategy for flow cytometry analysis.
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Hangai, S., Kawamura, T., Kimura, Y. et al. Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells. Nat Immunol 22, 947–957 (2021). https://doi.org/10.1038/s41590-021-00967-5
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DOI: https://doi.org/10.1038/s41590-021-00967-5
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