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activation with an agonist CD40 monoclonal
CD40 Agonists Alter Tumor Stroma and antibody (mAb) can circumvent tumor-induced
immune suppression and invoke productive T
Show Efficacy Against Pancreatic cell–dependent antitumor immunity in PDA.
We first evaluated the clinical impact of CD40
Carcinoma in Mice and Humans activation by performing a clinical trial of the fully
human agonist CD40 mAb CP-870,893 (9) in
combination with gemcitabine chemotherapy
Gregory L. Beatty,1,2,6 Elena G. Chiorean,3 Matthew P. Fishman,1 Babak Saboury,5 (2′-deoxy-2′,2′-difluorocytidine) for patients with
Ursina R. Teitelbaum,2,6 Weijing Sun,2,6 Richard D. Huhn,4 Wenru Song,4 Dongguang Li,4 chemotherapy-naïve, surgically incurable PDA
Leslie L. Sharp,4 Drew A. Torigian,2,5 Peter J. O’Dwyer,2,6 Robert H. Vonderheide1,2,6* (10). We tested CP-870,893 with gemcitabine be-
cause chemotherapy delivered before an agonist
Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly CD40 mAb can facilitate enhanced tumor anti-
in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune gen presentation by APCs (11–14). Twenty-one
suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 patients (90% with metastatic disease) received
antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable gemcitabine weekly on days 1, 8, and 15 with
PDA and observed tumor regressions in some patients. We reproduced this treatment effect CP-870,893 administered on day 3 of each 28-
in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression day cycle (fig. S1). Treatment was well tolerated
required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly overall (fig. S2), and the most common side
infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, effect was mild-to-moderate cytokine release
cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our syndrome characterized by chills, fevers, rigors,
findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment and other symptoms on the day of CP-870,893
of cancer.
Abramson Family Cancer Research Institute, University of
ancreatic ductal adenocarcinoma (PDA) pothesizing initially that doing so would unleash

Pennsylvania School of Medicine, 421 Curie Boulevard, Phil-
remains an almost universally lethal dis- tumor-specific cellular immunity to eliminate PDA. adelphia, PA 19104, USA. 2Abramson Cancer Center, Univer-
sity of Pennsylvania School of Medicine, Philadelphia, PA
ease; chemotherapy offers minimal bene- Activation of the tumor necrosis factor (TNF) 19104, USA. 3Division of Hematology/Oncology, Department
fit over best supportive care for patients who are receptor superfamily member CD40 has been of Medicine, Indiana University School of Medicine, Indian-
not surgical candidates (1). We have previously shown to be a key regulatory step in the devel- apolis, IN 46202, USA. 4Pfizer Corporation, New London, CT
demonstrated that leukocytes actively infiltrate opment of T cell–dependent antitumor immu- 06320, USA. 5Department of Radiology, Department of Med-
the stromal compartment of PDA, even at the nity, which relies on CD40-mediated “licensing” icine, University of Pennsylvania School of Medicine, Phila-
delphia, PA 19104, USA. 6Division of Hematology-Oncology,
earliest stages of tumor development, and or- of antigen-presenting cells (APCs) for tumor- Department of Medicine, University of Pennsylvania School of
chestrate an immune reaction that is immuno- specific T cell priming and activation (3–8). Medicine, Philadelphia, PA 19104, USA.
suppressive (2). In this study, we investigated On the basis of this premise, we investigated *To whom correspondence should be addressed. E-mail:
the reversibility of this immune suppression, hy- in both humans and mice whether systemic CD40

1612 25 MARCH 2011 VOL 331 SCIENCE

17). 870. gemcitabine induced tumor regression in 30% of out of 21 patients developed a partial response phages with an absence of lymphocytes (Fig. 2018 col after one dose of CP-870. fore modeled our clinical study in KPC mice by as a measure of an on-target biological effect duction in the primary pancreatic lesion. (C) Histopathology of a biopsied metastatic lesion [from patient 10031016 (left)] and a surgically resected primary pancreatic lesion [from patient 10061003 (right)]. To test whether CD40 im- grade 4 cerebrovascular accident but recovered filtrate devoid of lymphocytes (Fig. cycles of therapy. S4) (10).6-cm hepatic metastasis. a historical tumor response rate of 5. 2A). bine weekly with the agonist CD40 mAb FGK45 Evaluation Criteria in Solid Tumors (RECIST) and 47% reduction in the one remaining hepatic administered 48 hours after the first infusion of assessment. com. plantable tumor models. FGK45 induced the was 7.893 because of a resected primary lesion revealed a cellular in. Scale bars. with the longest dimension annotated. Upon biopsy after four gemcitabine. mice (Fig. with 6 and p53R172H alleles in pancreatic cells (15). 1C). tures of human PDA (15). Seven days after treatment with FGK45. and posttherapy CT imaging antitumor activity is dependent on T cells (6–8).8 months). We there- tomography–computed tomography (PET-CT) One patient with a PR showed a 46% re. Arrows (right) identify polymorphonuclear infiltrating cells without lymphocytes. Arrows (left) indicate a macrophage-dominated inflammatory infiltrate within extensive tumor necrosis. Such munotherapy is dependent on T cell activation. Metabolic responses were observed metastasis (Fig. both was not obtained. cell immunity (18). One of these patients (pa. 1. 11 patients had stable disease (SD). for tumor response. 1A). CD4+ and CD8+ T cells of KPC mice acquired survival (PFS) for the 21 patients was 5. we turned to a spon. pancreatic lesion.6 months mediated tumor regression. **Patient 10031001 did not obtain posttherapy scans because of clinical deterioration from disease progression after one dose of CP-870. and managed in the outpatient clinic with sup. Instead. Therefore. however. of 21 patients alive. static lesions in 88% of patients evaluated after showed no viable tumor. patient 10061003 underwent surgical resection of the primary tumor after 12 cycles of therapy. 4. 50 mm. 4 necrosis and an infiltrate dominated by macro. S3). ment mechanisms in patients (16. S5A). the KPC model is standard modalities: (i) [18F]2-fluoro-2-deoxy. 1B). cluding interferon-g (IFN-g) and interleukin IL- mable). evaluating the therapeutic efficacy of gemcita- of therapy and (ii) CT imaging for Response plete resolution of a 7. metastases and a 64% reduction in the primary Activation of the CD40 pathway is a critical tient 10031010) was taken off the study proto. The primary pan- creatic tumor and two metastatic liver lesions are marked by arrows.sciencemag. taneous mouse model of PDA.893 but restarted gemcitabine alone and achieved a PR. By RECIST. Treatment with FGK45 alone 4 patients had progressive disease (PD) (Fig. *Patient 10061001 was defined as PD because of the appearance of a new nontarget lesion.893 and gemcitabine showed therapeutic thought to be relevant for understanding treat- D-glucose (FDG) avidity on positron emission efficacy in patients with metastatic PDA. Agonist CD40 mAb in combination with gemcitabine 10031016 10061003 induces clinical responses in patients with surgically incurable PDA. this remaining liver lesion three-dimensional ultrasonography (fig. neurologically and restarted gemcitabine alone tumor regression without lymphocyte infiltration we examined the function of T cells isolated and achieved a PR. Histological analysis of the event in the development of tumor-specific T Downloaded from http://science. Symptoms were transient (<24 hours) on interim data as of 25 August 2010. REPORTS infusion. The second patient (patient was unexpected on the basis of results from im. Median PFS and OS are based conditional expression of both mutant KrasG12D the absence of CD4+ or CD8+ cells or both CD4+ A B Fig. similar to the objective response (PR).7 months (1).0 months to not esti.sciencemag. an increased capacity to secrete cytokines. 5. The median progression-free Therefore. Gemcitabine alone achieves Because immunocompetent KPC mice sponta- portive care. and 1C). Patient 10031016 underwent tumor biopsy after completing four cycles of SCIENCE VOL 331 25 MARCH 2011 1613 . where CD40-induced and peripancreatic lymph nodes) of KPC mice. Two patients were not evaluable on study achieving a complete resolution of all hepatic whereas gemcitabine alone did not (Fig.4 months (95% confidence interval.3 months and median OS of fidelity to the histopathologic and molecular fea- metastatic lesions was evaluated using two 5. and the median overall survival (OS) The KPC model of PDA is a genetically 17A (fig. with neously develop PDA tumors that display high The impact of therapy on the primary and median PFS of 2. Tumor response was monitored by by FDG–PET-CT in both the primary and meta. from the spleen and pancreas (including tumor 10031001) had clinical deterioration from dis.893. arrowheads mark tumor cells. ease progression.5 engineered mouse model that incorporates the same rate of tumor regression in KPC mice in to 12. (B) CT imaging obtained at baseline and end of cycle 3.4%. to understand the mechanism of on January 22. we observed We found that the combination of FGK45 with two cycles of therapy (fig. C Liver Metastasis Primary Tumor (A) Best overall percentage of change from baseline in tumor target lesion measurement shown as a waterfall plot. A second patient with a PR underwent rate in our patients. treatment with CP. Both patients achieved a PR. in- (95% confidence interval. 2A). surgical resection of the primary tumor after resulted in the same rate of tumor regression. www. ***Patient 10031010 came off the study after one dose of CP-870.

(A) KPC mice were treated with gemcitabine or phosphate- buffered saline (PBS) on day 0 and day 7.05. and 10. with control IgG2a or FGK45 administered on day 2.43: P < 0. (H) A heat map displaying the flow cy- tometric analysis of tumor- associated macrophages from individual KPC mice (columns) for expression of cell surface molecules (rows) 3 days after treatment with control IgG2a number of standard deviations from the mean. (H).sciencemag.5 + 2. Thus. Antitumor activity of A agonist CD40 mAb in KPC mice is T cell–independent. Agonist CD40 A H mAb targets systemic macrophages before their infiltration of tumor. 7. scale bars. Error bars in (A) repre- sent on January 22. 50 mm. which was determined from compared with FGK45. Im- munohistochemistry was used to quantify leukocyte infiltration (A) into peri- pancreatic lymph nodes (A. B to E). not with surface molecule expression. S5. and (I) were defined as FGK45-treated mice that demonstrated tumor regression by ultrasound analysis. Moreover. This was unexpected ilar overall. 1. E. 2. B and C). Instead. CD3+ T cells appearance of tumors from responder compared after treatment with FGK45 (Fig. and G) by staining with a bio- tinylated goat antibody directed against rat IgG to detect FGK45 or RB6- 8C5 bound to cells at 10 min (A) to (D) or 18 hours (A) and (E) to (G) after treatment. 2. 2.43: P < 0.05. (Top) The percentage of tumor-associated macrophages treatment with control IgG2a. Responders (D).43 antibodies. respectively. gemcitabine + FGK45: P < 0.05. CD3+ T cells were not observed to infiltrate tu. FGK45-treated mice with tumor progression by ultrasound were defined as nonresponders (C) and (G). F to H). Fig. Percent change in tumor volume from day –1 (baseline) to day +14 is shown for each mouse as a B waterfall plot (in comparison with PBS + IgG2a. FGK45 + GK1. REPORTS and CD8+ cells (Fig.00. Macrophages were depleted with CELs before FGK45 treatment (A) and (G).05. 0.5 and 2. gemcitabine + IgG2a: P = 1. smaller in responder animals ( . FGK45 + GK1. tu- mor. Hematoxylin and eosin (H&E) histology [(B) to (E)] and CD3 immunohistochemistry [(F) to (I)] are shown for tumors from KPC mice treated with IgG2a (B and F) or FGK45 (C to E and G to I). and F) and KPC tu- mor (A. C. B. 2. tivation and the development of productive anti. PBS + FGK45: P < 0. 50 mm. FGK + 2. LN.sciencemag. E and I). 1614 25 MARCH 2011 VOL 331 SCIENCE www. nd. Downloaded from http://science.05. (Bottom) Mean fluorescence intensity as the determined. Scale bars. Histopathological mors in KPC mice at baseline or at any time with peripancreatic lymph nodes. 2018 3. activation of Fig. P values are based on Student’s t test. Cohorts of KPC mice re- ceiving treatment with FGK45 were also depleted of CD4+ or CD8+ cells or both CD4+ and CD8+ cells with the use of GK1. T. on days –1. 3. CD3+ T cells remained localized to therapy (fig. peripan- creatic lymph node. 2A). D. Fisher’s exact test). when the whole pancreas was resected en bloc tumor T cell immunity (6–8). with the exception that tumors were peripancreatic lymph nodes situated adjacent to given the established link between CD40 ac.5: P < 0. did not change in frequency before and after with nonresponder animals at day 14 was sim. (E). developing tumors (Fig.

Within 2 to To determine whether FGK45 binds to macro. B cells. KPC mice were treated with CELs. By immuno. and immunohistochemistry for treatment with control IgG2a (top panel) or FGK45 (bottom panel).org SCIENCE VOL 331 25 MARCH 2011 1615 . A and G). in contrast to RB6-8C5. S7. 50 mm. We observed class II molecules compared with splenic macro- used as a control and specific for Gr-1 expressed no change in the frequency of macrophages in phages from tumor-bearing KPC mice and nor- on granulocytes and immature myeloid cells in the pancreas after FGK45 treatment (fig. duced a transient depletion of macrophages from after treatment (Fig. Shown is a representative assay from KPC tumors were analyzed 18 hours after treatment with control IgG2a (D. phages (fig. 3D). (D) to (L) collagen I [(H). A and B). FGK45.05. tissue macro.sciencemag. binding of FGK45 to leukocytes within the tumor activated and capable of secreting IL-10. Means T SD are F. When histochemistry. which bound leuko. (21. and I). S8B). and F. S9. microenvironment. macrophages the peripheral blood. FGK45 was found initially tumors (Fig. and pan. CD40 activated C tumor-infiltrating mac- rophages mediate tumor regression. and fig. S6). do not deplete macro- be found on some tumors (19). 4. 22). particularly F4/80+ tumor. FGK45 + CELs: P = 1. The found that tumor-associated macrophages were peripheral blood macrophages. (fig. *P < 0. mal littermates (fig. we found that PDA cells were siding within the spleen. FGK45 was not found on the cell sur. and IL-6 but had reduced expression of MHC Downloaded from http://science. 3. To test infiltrating the tumor but not lymph nodes (Fig. TNF-a. S11. FGK45 in. CD40-negative. In the absence of any treatment.05. A and C).sciencemag. After treatment with peripheral blood (fig. (G). phages within tumors (fig. microenvironment was found to occur in clus. In liposomes (CELs) to deplete systemic macro- model. whereas cells in the tumor stroma creas of KPC mice (fig. or FGK45 + CEL (J. grate into tissues.00. FGK45: P < 0. and (K)]. S7. (C) Cleaved caspase 3 expression on hematoxylin-and-eosin histology (D. cytes in the tumor periphery as early as 10 min gration into tumors. FGK45 binds to macrophages before their mi- Within 18 hours of administration. Within the tumor FGK45 labeling was no longer detectable in the expressed CD40. Shown are depicted. (A) KPC mice were treated with control IgG2a or FGK45 or FGK45 plus depletion of systemic macrophages by means of CELs. was observed bound to F4/80+ macrophages can either promote or inhibit tumor progression lation in the spleen (fig. FGK45 (E. and H). K. (B) F4/80+ tumor-associated macrophages were isolated from KPC mice that had been treated with FGK45 (blue squares) or control IgG2a (green circles) and incubated with KPC- derived tumor cell lines. with subsequent accumu. which then mi. Masson’s trichrome stain to reveal KPC tumors was determined by immunohistochemistry 18 hours after extracellular matrix in blue [(F). We therefore to localize to peripancreatic lymph nodes (Fig. we compared the on January 22. Instead. and L). sues (20) and. Tumor cell death in vitro was measured by 7-aminoactinomycin D (7-AAD) labeling and flow cytometric analysis at 24 hours. presence of CD40+ macrophages within the tu- investigated the impact of CD40 immuno. we whether CD40 mAb initially engages CD40 on 3. A and B) and not the tumor (Fig. Student’s t test. REPORTS the CD40 pathway does not trigger T cell infil. S12). S10). lymph nodes. C and D). contrast. FGK45 Depending on their phenotype. and dendritic cells and can also binding to CD40 (fig. At 18 hours. Fisher’s exact test). a mAb ters of cells rather than diffusely. S8A). www. Shown is a water- fall plot displaying per- cent change in tumor volume from baseline to day +14 (in comparison with IgG2a. S8A) nor was FGK45 internalized after by capillary walls. Gr-1+ cells in the peripheral blood were treated KPC mice with clodronate-encapsulated productive antitumor T cell immunity in the KPC found to be coated with antibody (fig. we tration into tumors and is insufficient to induce 8C5. however. (I). 3. E. These findings support the hypothesis that therapy on F4/80+ macrophages in KPC mice. 10 min after systemic administration of RB6. B and C). S9A). E. and (L)]. at 10 min. 2018 tion of FGK45 with that of RB6-8C5. Scale bars. CELs do not diffuse into tis- phages. phages before their infiltration of tumors. A. J). S11A). 3. G. B to E). Because liposomes are not CD40 is expressed on a wide range of face of F4/80+ macrophages in peripheral blood capable of traversing vascular barriers produced leukocytes including monocytes. macrophages in KPC tumors and spleens A B Fig. therefore. FGK45 was observed bound to leukocytes re. mor. two independent experiments each performed in triplicate. despite the continued associated macrophages (fig.

13 mm (mean T SD. K. 2Marine Biological Labora- with constriction zones and was required for assembly of 17-nanometer-diameter filaments. Mechanistically.(6) or re- cycling endosome (7 )–derived vesicles establish Abscission Involves Helices membrane separation from within the intercel- lular bridge. but it may involve mechanical tearing (4 ) followed by *To whom correspondence should be addressed. CD40 acti. in KPC animals (fig. CA076931 ( (D. with Pfizer Corp. H. S13 and S14). In KPC mice depleted of systemic 1.1. the capacity of FGK45 to induce tumor regres. D-01307 large membrane structures. 5Medical Theoretical Center. References lethal tumor for which new therapies are crit. J. Di Rosa.) 1616 25 MARCH 2011 VOL 331 SCIENCE www.. 118. References and Notes 4. J. Med.B. turning to baseline after 7 days (Fig. Nature 393. A. In this study. Zitvogel et al. D-82152 the abscission site. 20. Nat. R. C. by itself. 23. L. 2 (2000). Furth. 1991 (2008). patented by Pfizer Corp. A. M. been previously described (22). Torigian played a decrease in collagen I content. D-01307 Dresden. 14. 1457 (2009).J. Germany. 19. Li.gerlich@bc.. 5. 3Department of Biology. Invest.L. Sharp are employees of Pfizer Corp. 4. Some of the clinical data were presented to induce stromal degradation (Fig.. with elevated serum levels of IL-12. A. P. P.H. Offringa. 16. B. H. I. 1. on January 22. Meeting. Curr. These regions dis. June. of ESCRT-III–Dependent Filaments To clarify which events lead to abscission. MA 02543. 5. showed efficacy against PDA. and involution (Fig. Center for Integrated Protein Science Munich. 231 sion (Fig. Woods Hole. Nat. (2010). USA. Nat. Lake. E. Gabrilovich.. E. D. R. and B. Our results emphasize that tumor immu. Clin. mueller-reichert@ tu-dresden. Cancer Res. Abrams. Vonderheide et al. C. 478 (1998).1126/science. Pfotenhauerstrasse 108. E. 15. Although now at a new address. van Kooten.ethz. 1083 (2007). D. We identified helices of 1 Institute of Biochemistry. in both mice 13. A. Robinson. their role has 17. 8. Med.H. TNF-a. B. Sanders. H. Glennie. Grosshaderner Strasse 2.. IFN-g. 67. D. 548 (1999).W. which manages its distribution. Diehl et al. 876 29 September 2010. discussions. 480 (1998). Clin. Macrophages isolated from the munity in PDA after CD40 activation will re. van der Voort. 4490 (2003). Switzerland. 4C). W. by the CD40 pathway can be harnessed thera. pancreas of tumor-bearing KPC animals treated quire modulation of additional tumor and host 24. Robinson. CD40 12. in vivo with FGK45 lysed tumor cells in vitro factors or the incorporation of novel vaccines G. F. Med. Oncol. R. Schafmattstrasse single stalk. J. Lancet Oncol. O’Dwyer discloses receiving honoraria from Pfizer. 2018 sociated fibrosis appeared to be undergoing that target inflammatory cells and stroma within Pfizer Corp (to R. three-dimensional structured illumination microscopy. This finding correlated with in vivo (23). peutically to restore tumor immune surveillance 474 (1998). Bennett et al. Biol. E. R. R. which narrowed the cortex of the intercellular bridge to a Federal Institute of Technology Zurich (ETHZ). C. Opin. L. The identification of contractile filament helices at the intercellular bridge Planegg-Martinsried. R. A. 5. The endosomal sorting complex required for transport (ESCRT)–III co-localized 18. and highly 8. A.O. Nature 420. antitumor immunity. REPORTS in tumor-bearing KPC mice up-regulated MHC unappreciated role for the CD40 pathway in 10. Swiss 17-nanometer-diameter filaments. Germany. 976 (2010). 469 (2005). 2 (2007). Methods 174. 2403 (1997). Rev. P.1 Ina Poser. velopment of emerging therapeutic strategies preclinical studies were supported by funding from Downloaded from http://science. Clark et al. A. These changes coincided with a agonists altered tumor stroma and. R. at the 2010 American Society of Clinical Oncology Annual These findings identify a novel mechanism where. Germany.) and by NIH grants P30 CA016520 (P. but not IL-10. and humans. E.G. regions of the tumor stroma and as. 145 (2001). CP-870.. We thank C. An al- Cortical Constriction During ternative model proposes that Golgi.2* bridge. 774 (1999). Van Rooijen. S.). S. Nowak.3 Jana Mäntler. and though tumor-suppressing macrophages have 16. Department of Biology. and P. Clin. J. C. mice with CELs. Supporting Online Material www. Coussens. 19. I. 22. J.. P. and we 21.-R. Materials and methods are available as supporting class II and the costimulatory molecule CD86 regulating the immune reaction and fibrosis material on Science Online. French. 11. J. M. At the intercellular Heinrich Leonhardt. Cancer Res. Ridge. H and I). PDA is a common. Immunol. accepted 14 February 2011 ically needed. This research was supported by the Abramson observations of cleaved caspase 3 expression in nosurveillance can at times be governed strictly Family Cancer Research Institute of the University of focal areas of the tumor at 18 hours after treat. 22. Science 324. The clinical study and part of the treatment. 4B). Schoenberger. Melief. Simon. E. Leukoc. necessary for CD40-mediated tumor regression. R. 4.. Nature 393. associated macrophages. insufficient for invoking 83 (1994).893 is owned and ent with degradation of the tumor matrix (Fig. A and B) (8). 4A). 4Max Planck Institute for Mole- has broad implications for the understanding of cell division and of ESCRT-III–mediated fission of cular Cell Biology and Genetics. by innate immunity under the regulation of the Pennsylvania School of Medicine (R.. Olive et al.5. 780 (1999).) and K12 ment with FGK45 (Fig. C. Z. CH-8093 Zurich. J. D. Oncol.D).sciencemag.V. Clin. Nat. Chan.M. Sica. T. Van Dyke. Matzinger. Tutt. tory (MBL). by targeting tumor-infiltrating macrophages in. Mantovani. cytokine surge on day 1 after FGK45 treatment. A. we imaged live HeLa cells stably expressing enhanced green fluorescent protein (EGFP)–a- Julien Guizetti. R. FGK45 treatment failed 2. Nat. Figs. Cancer 5. Werb. during the conduct and analysis of this study. 10.4 Sandra Maar. . and figs. Cancer Res. Materials and Methods volved in cancer inflammation. hypothesize that full engagement of T cell im. with expression levels peaking at day 3 and re. Ludwig Simultaneous spastin-mediated removal of underlying microtubules enabled full constriction at Maximilians University Munich. owns stock in Pfizer. 3. To determine whether macrophages were been largely linked to the orchestration of T cell 18. Keith. Lake.4 tubulin (Fig. Immunol. S15). At this time after CD40 pathway and support the continued de. associated with PDA by reeducation of tumor. L.. we depleted systemic macrophages from KPC vation was. 860 (2002).2* Daniel W. and electron tomography. E-mail: daniel. the tumor microenvironment. K. J. 397 (2005).97 T 0. devastating.V. Clin. S1 to S15 7. Huhn was affiliated macrophages using CELs. W. H. J. The mechanism of A of cell division in animal cells whereby the two daughter cells are physically abscission is poorly understood (1–3). Here. and R. R. 4. Banchereau. Sotomayor et al. Medical Faculty Carl Gustav Carus.). Al. J. Gerlich1. Song. consist. Fetscherstrasse 74. 63. Treatment with CELs abolished productive antitumor T cell immunity. 5. 25.biol. Burris 3rd et al. n = After partitioning of cytoplasmic contents by cleavage furrow ingression.1198443 plasma membrane wound healing (5).H. L. microtubule bundles gradually narrowed to a diameter of 0. Hingorani et al.sciencemag. Dresden University of Technology. 9. Our findings identify a previously (2007). Oncol. W. Stanger for helpful (Fig. M. we examined intermediate stages of abscission in human cells by using live imaging. 3H. S. P. R. T. 67. L. Koretzky. 15. M. D to G). Vonderheide.3 Thomas Müller-Reichert.. Jaffee et (T.V. 13. which subsequently splits by abscission. B.2 Lothar Schermelleh. J. bscission represents the very final step severed from one another. 9518 (2007). Nature 393.J. J to L). 6. Toes. animal cells remain 17 cells) and then disassembled on one side connected by an intercellular bridge. L. Cancer Cell 7. Dresden.sciencemag. PERMISSIONS http://www. Leslie SUPPLEMENTARY http://science. Dongguang Li.CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans Gregory L. The title Science is a registered trademark of AAAS.1198443 Downloaded from http://science. Wenru Song.full REFERENCES This article cites 22 articles. O'Dwyer and Robert H. 1612-1616.abstract CONTENT http://science. Teitelbaum. 1200 New York Avenue NW. Chiorean. 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