scholarly journals 144 SIRPα deficient CAR-Macrophages exhibit enhanced anti-tumor function and bypass the CD47 immune checkpoint

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A152-A152
Author(s):  
Chris Sloas ◽  
Rashid Gabbasov ◽  
Nicholas Anderson ◽  
Sascha Abramson ◽  
Michael Klichinsky ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Phenotypic Characterization ◽  
Target Cells ◽  
Macrophage Cell ◽  
Downstream Signaling ◽  
The Impact ◽  
Anti Tumor Activity

BackgroundAdoptive macrophage cell therapy represents a novel approach for cancer immunotherapy. Macrophages engineered to express chimeric antigen receptors (CAR-M) have shown promising pre-clinical results against solid tumors by improving tumor clearance, overall survival and facilitating the remodeling of the tumor microenvironment to induce a potent adaptive immune response. CD47 is a well-established macrophage immune checkpoint molecule that is over-expressed on tumor cells. CD47 binds to the macrophage signal regulatory protein α (SIRPα) to limit phagocytosis and macrophage effector functions. In this study we evaluated the impact of CD47 on CAR-M activity and showed that CD47-resistant targeted macrophage cell therapy mediates enhanced anti-tumor activity.MethodsCRISPR/Cas9 was used to deplete the cognate receptor SIRPα from primary human macrophages (>90% efficiency and >90% viability) to increase CAR-M function. To assess anti-tumor activity of CAR-M, < i >in vitro</i > co-culture assays were established with an anti- human epidermal growth factor receptor 2 (HER2) CAR and HER2+ tumor cell lines. Macrophage killing and phagocytosis of target cells were quantified in real-time using a genetically encoded fluorophore (to monitor tumor cell growth) or a pH-sensitive dye (to monitor phagocytic acidification). In parallel, phenotypic characterization of surface molecules, cytokine secretion levels, biochemical analysis of downstream signaling molecules and response to purified HER2 and CD47 protein stimulation were evaluated.ResultsSIRPα knockout (KO) alone failed to induce tumor phagocytosis and cytotoxicity but enhanced targeted CAR-M anti-tumor activity. This was demonstrated by a reduced time required to kill 50% of tumor cells and a 2-fold increase in phagocytic activity, indicating synergy between SIRPα KO and CAR stimulation. Furthermore, in the absence of SIRPα, enhanced cytokine/chemokine secretion, macrophage polarization, and downstream signaling were observed.ConclusionsWe show for the first time the feasibility of generating gene edited primary human CAR macrophages for therapeutic purposes, and demonstrate that SIRPα deletion enhances the targeted anti-tumor activity of CAR-M.

scholarly journals Tumor cell anti-oxidant defenses. Inhibition of the glutathione redox cycle enhances macrophage-mediated cytolysis

1981 ◽  
Vol 153 (4) ◽  
pp. 766-782 ◽  
Author(s):  
CF Nathan ◽  
BA Arrick ◽  
HW Murray ◽  
NM DeSantis ◽  
ZA Cohm
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Defense Mechanisms ◽  
Specific Activity ◽  
Protective Role ◽  
Target Cells ◽  
Redox Cycle ◽  
Oxidation Reduction ◽  
Glutathione Redox Cycle ◽  
Glutathione Redox

The basis of resistance to oxidative injury was studied in six murine tumor cell lines that differed 54-fold in their resistance to enzymatically generated H(2)0(2). The tumors varied 56.7-fold in their specific activity of catalase, 5.3-fold in glutathione peroxidase (GPO), 3.3-fold in glutathione reductase (GR), and 2.7-fold in glutathione. There was no correlation among the levels of the three enzymes, and tumor cell resistance to lysis by H(2)0(2). However, the logarithm of the flux of H(2)0(2) necessary to cause 50 percent lysis of the tumor cells correlated with their content of glutathione (r = 0.91). The protective role of glutathione was analyzed by blocking GR and GPO, the catalysts of the glutathione redox cycle. This was facilitated by the demonstration that the anti-neoplastic agent 1,3-bis-(2- chloroethyl)-l-nitrosourea (BCNU) was a potent inhibitor of GR in intact tumor cells. BCNU inactivated tumor cell GR with a 50 percent inhibitory dose of 11 μM and a t(l/2) of inhibition of 30 s. Complete inhibition of GR was attained with no effect on GPO or catalase. Tumor cells whose GR was inactivated by BCNU could be lysed by fluxes of H(2)0(2) to which they were otherwise completely resistant. They could be killed by phorbol myristate acetate (PMA)-stimulated, bacilli Calmette-Guerin-activated macrophages in numbers which were otherwise insufficient, and by nonactivated macrophages, which otherwise were ineffective. BCNU-treated target cells were also much more sensitive to antibody-dependent, macrophage-mediated cytolysis. However, such tumor cells were no more sensitive than controls to lysis by alloreactive T cells or by antibody plus complement. Next, we deprived tumor cells of selenium by passage in selenium-deficient mice. GPO was inhibited 85 percent in such cells, with no effect on GR or catalase. Tumor cells with reduced GPO activity were markedly sensitized to lysis by small fluxes of H(2)0(2) or by PMA-stimulated macrophages or granulocytes. In contrast, inhibition of catalase with aminotriazole had no effect on the sensitivity of three tumors to peroxide-mediated lysis, and had modest effects with two others. Thus, the oxidation-reduction cycle of glutathione serves as one of the major defense mechanisms of tumor cells against three related forms of oxidant injury: lysis by fluxes of H(2)0(2), by PMA-triggered macrophages, and by macrophages in the presence of anti-tumor antibody.

scholarly journals Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

1976 ◽  
Vol 143 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J W Schrader ◽  
G M Edelman
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Hybrid Origin ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

scholarly journals PD-L1 Checkpoint Blockade Augments Anti-Tumor Immune Response of GD2 or HER2-Bsab Ex Vivo Armed T-Cells (EVAT) Therapy in Osteosarcoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1959-1959
Author(s):  
Jeong A Park ◽  
Hong fen Guo ◽  
Hong Xu ◽  
Nai-Kong V. Cheung
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Bispecific Antibody ◽  
Ex Vivo ◽  
Activated T Cells ◽  
The Impact ◽  
Anti Tumor Activity

Background Ex Vivo Armed T-cells (EVAT) carrying zeptomoles (10-21M) of T-cell engaging GD2-bispecific antibody (GD2-EVAT) or HER2-bispecific antibodies (HER2-EVAT) have potent anti-tumor activity against GD2(+) and/or HER2(+) solid tumors. Strategies to further optimize this approach are highly relevant. PD-1 is a key immune checkpoint receptor expressed mainly by activated T-cells and mediates immune suppression by binding to its ligands PD-L1 or PD-L2. Upregulation of PD-L1 has been found in many cancers including osteosarcoma and associated with aggressive disease and poor outcome. While the use of immune checkpoint inhibitors (ICIs) seems logical, the ideal timing when combined with T-cell engaging bispecific antibody (T-BsAb) or EVAT has yet to be defined. Here, we described the effects of anti-PD-1 or anti-PD-L1 antibodies on GD2-EVAT or HER2-EVAT therapy and explored the impact of its timing in the treatment of osteosarcoma which is GD2(+), HER2(+) and PD-L1(+). Methods GD2-BsAb and HER-BsAb were built using the IgG(L)-scFv format (Can Immunol Res, 3:266, 2015, Oncoimmunology, PMID:28405494). T-cells from healthy volunteer donors were isolated, and cultured ex vivo in the presence of CD3/CD28 beads plus 30 IU/mL of interleukin 2 (IL-2). Between day 7 and day 14, activated T-cells (ATCs) were harvested and armed for 20 minutes at room temperature with GD2-BsAb or HER2-BsAb. In vivo anti-tumor activity against GD2(+), HER2(+), and PD-L1(+) osteosarcoma cell line xenografts was tested in BALB-Rag2-/-IL-2R-γc-KO mice. Anti-human PD-1 antibody (pembrolizumab, anti-PD-1) or anti-human PD-L1 antibody (atezolizumab, anti-PD-L1) were tested for synergy with GD2-EVAT or HER2-EVAT therapy. Results The PD-1 expression increased among T-cells that circulated in the blood, that infiltrated the spleen or the tumor after EVAT therapy. While anti-PD-L1 combination therapy with GD2-EVAT or HER2-EVAT improved anti-tumor response against osteosarcoma (P=0.0123 and P=0.0004), anti-PD-1 did not (all P>0.05). The addition of anti-PD-L1 significantly increased T-cell survival in blood and T-cell infiltration of tumor when compared to GD2-EVAT or HER2-EVAT alone (all P<0.0001). Treatment of GD2-EVAT or anti-PD-L1 plus GD2-EVAT downregulated GD2 expression on tumors, but anti-PD-1 plus GD2-EVAT did not. For the next step we tested the impact of different combination schedules of ICIs on GD2-EVAT therapy. Concurrent anti-PD-1 (6 doses along with GD2-EVAT therapy) interfered with GD2-EVAT, while sequential anti-PD-1 (6 doses after GD2-EVAT) did not make a significant effect (P>0.05). On the other hand, while the concurrent use of anti-PD-L1 did not show benefit on GD2-EVAT, sequentially administered anti-PD-L1 produced a significant improvement in tumor control when compared to anti-PD-L1 or GD2-EVAT alone (P=0.002 and P=0.018). When anti-PD-L1 treatment was extended (12 doses after GD2-EVAT), the anti-tumor effect was most pronounced compared to GD2-EVAT alone (P <0.0001), which translated into improved survival (P=0.0057). These in vivo anti-tumor responses were associated with increased CD8(+) tumor infiltrating lymphocytes (TILs) of tumor. Conclusion In the arming platform, large numbers of target-specific T-cells can be generated, and this EVAT therapy is a highly effective cellular treatment with high potency in preclinical models. In addition, the advantage of ex vivo cytokine release following T-cell arming and activation could reduce or avoid life threatening cytokine storm if such activation was to proceed in vivo. Adoptive T-cell therapy induced immune response upregulates the inhibitory immune checkpoint PD-1/PD-L1 pathway, and combination treatment with anti-PD-L1 antibody, especially when combined as sequential therapy and continuously treated, significantly improved anti-tumor effect of EVAT, partly through increase in CD8(+) TILs infiltration. Disclosures Xu: MSK: Other: co-inventors in patents on GD2 bispecific antibody and HER2 bispecific antibody. Cheung:Ymabs: Patents & Royalties, Research Funding.

scholarly journals CAFs affect the proliferation and treatment response of head and neck cancer spheroids during co-culturing in a unique in vitro model

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Mustafa Magan ◽  
Emilia Wiechec ◽  
Karin Roberg
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Head And Neck ◽  
Treatment Response ◽  
Tumor Cells ◽  
In Vitro Model ◽  
Tumor Spheroids ◽  
Vitro Model ◽  
The Impact

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors for which the overall survival rate worldwide is around 60%. The tumor microenvironment, including cancer-associated fibroblasts (CAFs), is believed to affect the treatment response and migration of HNSCC. The aim of this study was to create a biologically relevant HNSCC in vitro model consisting of both tumor cells and CAFs cultured in 3D to establish predictive biomarkers for treatment response, as well as to investigate the impact of CAFs on phenotype, proliferation and treatment response in HNSCC cells. Methods Three different HNSCC patient-derived tumor cell lines were cultured with and without CAFs in a 3D model. Immunohistochemistry of the proliferation marker Ki67, epidermal growth factor receptor (EGFR) and fibronectin and a TUNEL-assay were performed to analyze the effect of CAFs on both tumor cell proliferation and response to cisplatin and cetuximab treatment in tumor spheroids (3D). mRNA expression of epithelial-mesenchymal transition (EMT) and cancer stem cells markers were analyzed using qRT-PCR. Results The results demonstrated increased cell proliferation within the tumor spheroids in the presence of CAFs, correlating with increased expression of EGFR. In spheroids with increased expression of EGFR, a potentiated response to cetuximab treatment was observed. Surprisingly, an increase in Ki67 expressing tumor cells were observed in spheroids treated with cisplatin for 3 days, correlating with increased expression of EGFR. Furthermore, tumor cells co-cultured with CAFs presented an increased EMT phenotype compared to tumor cells cultured alone in 3D. Conclusion Taken together, our results reveal increased cell proliferation and elevated expression of EGFR in HNSCC tumor spheroids in the presence of CAFs. These results, together with the altered EMT phenotype, may influence the response to cetuximab or cisplatin treatment.

Macrophage Antitumor Activity Induced by the Antigenic Lymphoma L5178Y/DTIC Subline

1982 ◽  
Vol 68 (5) ◽  
pp. 365-371 ◽  
Author(s):  
Ornella Marelli ◽  
Alberto Mantovani ◽  
Paola Franco ◽  
Angelo Nicotin
Keyword(s):  
Antitumor Activity ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Peritoneal Macrophages ◽  
Leukemic Cells ◽  
Target Cells ◽  
Tumor Target ◽  
Growth Inhibitory

Murine leukemic cells, after in vivo treatment with antineoplastic drugs, have been shown to express new antigenic specificities that were not detectable on parental cells and that were heritable after the withdrawal of drug treatment. A study was conducted of macrophage antitumor activity triggered by LY/DTIC cells, a subline of LY murine lymphoma, antigenically altered by the drug DTIC. In vitro non-specific inhibition of tumor cell growth was exhibited by spleen and peritoneal macrophages from mice previously challenged with viable LY/DTIC. Peritoneal macrophages from LY/DTIC immune animals showed moderate, although significant lytic activity against unrelated tumor target cells. Supernatants from mixed lymphocyte-tumor cell cultures, in which LY/DTIC immune lymphocytes and LY/DTIC tumor cells had been cultured, rendered normal macrophages non-specifically growth inhibitory for tumor cells.

Latent Epstein-Barr Virus Infection of Tumor Cells in Classical Hodgkin's Lymphoma Predicts Adverse Outcome in Older Adult Patients

2009 ◽  
Vol 27 (23) ◽  
pp. 3815-3821 ◽  
Author(s):  
Arjan Diepstra ◽  
Gustaaf W. van Imhoff ◽  
Michael Schaapveld ◽  
Henrike Karim-Kos ◽  
Anke van den Berg ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Older Adult ◽  
Hodgkin’S Lymphoma ◽  
Epstein Barr Virus ◽  
Adult Patients ◽  
Hodgkin's Lymphoma ◽  
Barr Virus ◽  
Epstein Barr ◽  
The Impact

Purpose In classical Hodgkin's lymphoma (cHL), the impact of tumor cell Epstein-Barr virus (EBV) status on clinical outcome is controversial. Patients and Methods We assessed failure-free survival (FFS) and relative survival (RS) in 412 patients with cHL and age-defined subgroups in a population-based study in the northern Netherlands. Tumor cell EBV status was positive in 34%, and the median follow-up time was 7.1 years. Patients' median age at diagnosis was 35 years (range, 7 to 91 years), and 63% had Ann Arbor stage I or II, 24% had stage III, and 12% had stage IV disease. Results EBV status influenced 5-year FFS and RS only in patients from the age group 50 to 74 years. Five-year FFS was 60% in patients with EBV-positive versus 85% in EBV-negative tumors (P = .01). Five-year RS was 69% in patients with EBV-positive versus 82% in EBV-negative tumors (P = .03). After adjusting for histology, HLA class II expression by tumor cells, stage, presence of extranodal localizations and treatment, and the effect of positive EBV tumor status remained significant in FFS multivariate analysis (hazard ratio, 3.11; 95% CI, 1.28 to 7.53; P = .01). Conclusion This study indicates that treatment failure in older adult patients with cHL is associated with positive tumor cell EBV status.

PD-L1 expression of high grade glial tumors at diagnosis and change of expression status at recurrence.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2035-2035 ◽  
Author(s):  
Basak Oyan ◽  
Seyma Eren ◽  
Ozlem Sonmez ◽  
Ferda Ozkan ◽  
Kaan Yaltırak ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
High Grade ◽  
Cross Sectional ◽  
Glial Tumors ◽  
The Impact ◽  
Expression Status ◽  
Over Time

2035 Background: PD-L1 expression status is the main predictive factor for response to immune checkpoint inhibitors. PD-L1 status may change over time with the impact of therapies. The aim of this study is to determine if PD-L1 expression status changes in recurrent gliomas after chemoradiotherapy. Methods: Thirty eight patients with recurrent high grade gliomas who had surgical excision at least two times were included in this retrospective cross-sectional study. Nine patients were excluded because of the lack of appropriate pathology slides for pathologic evaluation. PD-L1 expression of 29 patients was evaluated by an expert pathologist with immunohistochemical methods. PD-L1 positivity was defined as expression in ≥1% of tumor cells. Change in PD-L1 expression status was defined as an absolute 5% difference between two resections. Results: Of the 29 patients, 15 patients (51.7%) had PD-L1 expression in ≥1% of tumor cells and 7 patients (24.1%) had PD-L1 expression in ≥10% of tumor cells. Tumor PD-L1 expression (defined as expression in ≥1% of tumor cells) was positive in 15 (51.7%) of 29 patients at diagnosis and at the time of recurrence. The PD-L1 status did not change in 17 patients (58.6%). 8 patients had PD-L1 negative tumors both at diagnosis and at recurrence, while 9 patients had PD-L1 positive tumors both at diagnosis and at recurrence. In 6 patients (20.7%) a negative-to-positive switch and in 6 patients (20.7%) a positive to negative switch were seen. Tumor PD-L1 expression increased in 7 of 29 patients (24.1%) and decreased in 9 of 29 patients (31.1%). PD-L1 expression remained stable in 13 of 29 patients (34.4%). The change in PD-L1 status over time was not statistically significant. Conclusions: More than 50% of high grade glial tumors express PD-L1 at diagnosis, so these tumors are good candidates for immune checkpoint inhibitors. The expression status changes in more than 40% of high grade glial tumors at recurrence, so immune responsiveness of glial tumors can be modified by treatments like chemotherapy and radiotherapy.

Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3302-3309 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Keith W. Kombrinck ◽  
Angela F. Drew ◽  
Timothy S. Grimes ◽  
John H. Kiser ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Potential ◽  
Thrombin Inhibitor ◽  
Tumor Dissemination ◽  
Hemostatic Factors ◽  
The Impact ◽  
Deficient Mice

Abstract Detailed studies of tumor cell–associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.

scholarly journals Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1757 ◽  
Author(s):  
Elisabet Cuyàs ◽  
Sara Verdura ◽  
Begoña Martin-Castillo ◽  
Tomás Alarcón ◽  
Ruth Lupu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Dietary Interventions ◽  
Metabolic Traits ◽  
Review State

One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system’s ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.

Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3302-3309 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Keith W. Kombrinck ◽  
Angela F. Drew ◽  
Timothy S. Grimes ◽  
John H. Kiser ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Potential ◽  
Thrombin Inhibitor ◽  
Tumor Dissemination ◽  
Hemostatic Factors ◽  
The Impact ◽  
Deficient Mice

Detailed studies of tumor cell–associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.

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