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Macrophages Eat Cancer Cells Using Their Own Calreticulin As a Guide: Roles of TLR and Btk

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Macrophages Eat Cancer Cells Using Their Own Calreticulin As a Guide: Roles of TLR and Btk Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk Mingye Fenga,b,c, James Y. Chena,b,c,1, Rachel Weissman-Tsukamotoa,b,c,1, Jens-Peter Volkmera,b,c,1,PoYiHoa,b,c, Kelly M. McKennaa,b,c, Samuel Cheshiera, Michael Zhanga, Nan Guoa,b,c, Phung Gipa,b,c, Siddhartha S. Mitraa, and Irving L. Weissmana,b,c,d,2 aInstitute for Stem Cell Biology and Regenerative Medicine, bLudwig Center for Cancer Stem Cell Research and Medicine, cStanford Cancer Institute, and dDepartment of Pathology, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Irving L. Weissman, December 30, 2014 (sent for review December 15, 2014) Macrophage-mediated programmed cell removal (PrCR) is an Btk results in its trafficking to the cell surface, where it can be important mechanism of eliminating diseased and damaged cells used to mediate PrCR of appropriate tumor cells. before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don’t-eat-me signals such as Results CD47, which binds macrophage signal-regulatory protein α to in- We performed phagocytosis assays by coculturing mouse bone hibit phagocytosis. Blockade of CD47 on tumor cells leads to phago- marrow-derived macrophages (BMDMs) and target human can- cytosis by macrophages. Here we demonstrate that the activation cer cells to examine the efficacy of PrCR under different con- of Toll-like receptor (TLR) signaling pathways in macrophages syn- ditions. To induce phagocytosis, we blocked CD47 on a human ergizes with blocking CD47 on tumor cells to enhance PrCR. Bru- colon cancer cell line (SW620) either by treating tumor cells with ton’s tyrosine kinase (Btk) mediates TLR signaling in macrophages. CD47-blocking antibodies or by directly knocking out CD47. Calreticulin, previously shown to be an eat-me signal on cancer Phagocytosis was increased significantly by knocking out the self- cells, is activated in macrophages for secretion and cell-surface ex- protective signal CD47 (SW620CD47KO)(Fig. S1) resulting from posure by TLR and Btk to target cancer cells for phagocytosis, even an imbalance of eat-me over don’t-eat-me pathways (Fig. 1A). if the cancer cells themselves do not express calreticulin. Treatment of SW620WT cells with anti-CD47 antibody elicited stronger phagocytosis which was reversed by Fc-receptor blockers immunosurveillance | programmed cell removal | to the same level as that of SW620CD47KO cells, suggesting that Bruton’s tyrosine kinase | “eat me” signal | Toll-like receptor anti-CD47 antibody induced phagocytosis of SW620 cancer cells by both Fc-independent (blockade of CD47–SIRPα interactions) rogrammed cell removal (PrCR) is a process of macrophage- and Fc-dependent mechanisms (Fig. 1A). Pmediated immunosurveillance by which target cells are rec- To understand the molecular mechanisms of PrCR, we per- ognized and phagocytosed (1). PrCR previously was known to be formed screening experiments to identify signaling pathways that a key step concurrent with programmed cell death for the regulate the phagocytic ability of macrophages. TLR signaling clearance of apoptotic cells, but when apoptosis is blocked, PrCR plays a crucial role in the innate immune response against of neutrophils that are living (because of the enforced expression of bcl2) occurs precisely at the same time that PrCR removes Significance dying wild-type neutrophils (2). Recently a role for PrCR in eliminating living tumor cells has been revealed (1). Several studies have indicated a crucial function of CD47 as an antiphagocytic Macrophage-mediated programmed cell removal (PrCR) plays don’t-eat-me signal dominating over PrCR (3–10). During cancer an essential role in tumor surveillance and elimination. Blockade of the don’t-eat-me signal CD47 on tumor cells allows INFLAMMATION development, tumor cells up-regulate CD47, which protects them IMMUNOLOGY AND already expressed eat-me signals to induce PrCR to eliminate from PrCR (1, 3, 4, 6). Blockade of the interaction between CD47 tumor cells. To date the molecular mechanism by which mac- ontargetcellsanditsreceptor, signal-regulatory protein α (SIRPα), rophages recognize and phagocytose tumor cells remains un- on macrophages elicits efficient PrCR of cancer cells but not of A clear. This paper demonstrates that the activation of Toll-like most normal cells in vitro and in vivo (Fig. 1 ) (1, 3). When receptor (TLR) pathways in macrophages induces the phos- CD47 is blocked, cancer cells, but not normal cells, are phago- phorylation of Bruton’s tyrosine kinase (Btk), which catalyzes cytosed because prophagocytic eat-me signals such as calreticulin cell-surface exposure of calreticulin. Calreticulin on or secreted (CRT) are commonly expressed on many leukemias, lymphomas, by macrophages plays a critical role in mediating adjacent tu- and solid tumors (Fig. 1A) (11). CRT normally is an endoplasmic mor cell recognition and phagocytosis. These findings reveal reticulum (ER) protein possessing ER retention KDEL se- a strategy to enhance the efficacy of PrCR through a combina- quences but can be released to the cell surface in many instances tion of TLR/Btk activation and CD47 blockade, and advance our of cell damage by cytotoxic drugs or inflammation and is rec- understanding of the underlying mechanism of macrophage- ognized by macrophage LRP1/CD91 during phagocytosis of mediated PrCR of tumor cells. apoptotic cells (12, 13). Bruton’s tyrosine kinase (Btk) is a member of the Tec nonreceptor protein tyrosine kinase family, Author contributions: M.F., J.Y.C., R.W.-T., J.-P.V., P.Y.H., K.M.M., S.C., M.Z., N.G., P.G., S.S.M., which plays a crucial role in the regulation of the innate immune and I.L.W. designed research; M.F., J.Y.C., R.W.-T., J.-P.V., P.Y.H., K.M.M., M.Z., N.G., P.G., and S.S.M. performed research; M.F., J.Y.C., P.Y.H., K.M.M., M.Z., and N.G. contributed response (14, 15). A defect of Btk leads to immunodeficiencies new reagents/analytic tools; M.F., J.Y.C., R.W.-T., J.-P.V., P.Y.H., K.M.M., S.C., M.Z., N.G., including X-linked hypo- or agammaglobulinemia (16–18), pre- P.G., S.S.M., and I.L.W. analyzed data; and M.F., J.-P.V., and I.L.W. wrote the paper. sumably caused by the blockade of B-cell development and The authors declare no conflict of interest. perhaps related to inefficient clearance of defective B-lineage Freely available online through the PNAS open access option. cells as well (19). Thus far, however, little is known about the 1J.Y.C., R.W.-T., and J.-P.V. contributed equally to this work. molecular mechanisms by which macrophages recognize and 2To whom correspondence should be addressed. Email: [email protected]. phagocytose living cancer cells. We show here that macrophages This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. express CRT and that Toll-like receptor (TLR) signaling through 1073/pnas.1424907112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1424907112 PNAS | February 17, 2015 | vol. 112 | no. 7 | 2145–2150 Downloaded by guest on September 27, 2021 Fig. 1. Activation of TLR signaling leads to enhanced PrCR of living cancer cells. (A, Left) Schematic showing PrCR of living tumor cells by macrophages. Blockade of CD47 leads to an imbalance of eat-me over don’t-eat-me pathways, which elicits phagocytosis of tumor cells, either Fc-dependent (elicited by Fc– FcR interaction) or Fc-independent (labeled in red, representing cancer-specific eat-me signals other than Fc). (Right) A phagocytosis assay showing blockade of CD47-induced phagocytosis, with SW620 cells [control IgG-treated, anti-CD47 antibody (B6H12)–treated, or CD47KO] as target cells and BMDMs from − − − − RAG2 / , γc / mice. Fc receptor blocker (FcRB) reversed phagocytosis of B6H12-treated cells to the same level as inf CD47KO cells. **P < 0.01, t test; ns, not significant. (B) A phagocytosis assay showing a screen of TLR agonists, with SW620 cells [PBS-treated, anti-CD47 antibody (Hu5F9-G4)–treated, or CD47KO]as target cells and BMDMs from BALB/c mice. TLR agonists used in the screen were Pam3CSK4 (Pam, TLR1/2), heat-killed Listeria monocytogenes (HKLM, TLR2), poly (I:C) HMW [poly (I:C), TLR3)], lipopolysaccharide (LPS, TLR4), flagellin from Salmonella typhimurium (FLA-ST, TLR5), Pam2CGDPKHPKSF (FSL-1, TLR6/2), imiquimod (Imi, TLR7), and class B CpG oligonucleotide (ODN 1826, TLR9). Dashed lines indicate twofold phagocytosis of each condition [PBS-treated, anti- CD47 antibody (Hu5F9-G4)-treated, or CD47KO] in the control macrophage group. Error bars represent SD. pathogens (20, 21), and TLR agonists are listed as immunother- 2B). Notably, basal-level phagocytosis of cancer cells was regu- apeutic agents with anticancer potential (22). However, the role of lated by the Btk pathway, and ibrutinib showed an inhibitory TLR signaling in PrCR of living cancer cells remains unexplored. effect on both Fc-dependent and -independent phagocytosis Thus, we pretreated BMDMs with various TLR agonists and then (Fig. S6A). In sum, Btk is a crucial effector through which TLRs assayed their phagocytotic ability against cancer cells. We found mediate tumor cell phagocytosis. Interestingly, stimulation that the activation of multiple TLRs significantly enhanced and inhibition of Btk showed differential temporal effects on phagocytosis of cancer cells (Fig. 1B). We next focused on the phagocytosis. Maximal phagocytic ability of macrophages was TLR agonists that were most effective at enhancing phagocyto- achieved with 16 h of Btk activation (Fig. 2C); in contrast, blockade sis, assessing their effects on a wider range of macrophages and of Btk showed a prompt effect and reached the maximal inhibition tumor cells. We showed that treatment of macrophages with TLR3, within 1 h (Fig.
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