scholarly journals Immune Checkpoint Inhibitors (ICI) Enhance Cancer Associated Thrombosis (CAT) in Murine Model of Colon Carcinoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 779-779
Author(s):  
Shadi Swaidani ◽  
Young Jun Shim ◽  
Patricia Rayman ◽  
Paul G. Pavicic ◽  
C. Marcela Diaz-Montero ◽  
...  
Keyword(s):  
Murine Model ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Histone H3 ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Isotype Control ◽  
Flow Restriction ◽  
Tumor Bearing ◽  
Cancer Associated Thrombosis

Abstract Abstract Background: Venous thromboembolism (VTE) is an important immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICI) cancer therapy. To better understand the pathogenesis of ICI-induced VTE during ICI treatment, we utilized a murine model of cancer associated thrombosis (CAT) to examine the impact of ICI treatment on the development of flow restriction-induced thrombosis. Methods A syngeneic colon carcinoma murine model (CT26) on BALB/c background was utilized to evaluate venous thrombosis following inferior vena cava (IVC) ligation. Non-tumor-bearing and tumor-bearing animals were treated with therapeutic doses of ICI: anti-programmed cell death receptor 1 antibody (anti-PD1) and cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) or isotype control antibodies. Mice underwent surgical treatment for IVC ligation followed by surgical retrieval of thrombus. Western blot analysis was performed on plasma cleaved high molecular weight kininogen (cHK), and citrullinated histone H3 (CitH3). Results Tumor-bearing mice undergoing IVC ligation after anti-PD1 and anti-CTLA4 infusion developed larger thrombi compared to mice treated with isotype control IgG. Thrombus weights in CT26 tumor-bearing mice treated with ICI (19.56±4.41 mg) were significantly increased compared to those in mice treated with isotype control IgG (14.67±2.76 mg) (P=0.043). The weight of thrombi in non-tumor-bearing mice was not affected by ICI treatment (9.25±2.22 mg with control IgG vs 9.33±1.15 mg with ICI). In addition, there was a significant increase in thrombus length in mice treated with ICI (9±1.02 mm vs 7.61±0.99 mm with IgG, P=0.039). Cleaved high molecular weight kininogen (cHK), an indicator of contact activation was increased in plasma pre-IVC occlusion from ICI-treated mice compared to IgG-treated mice (68% vs 38% in HK cleavage). Citrullinated histone H3 (CitH3), a NETosis marker, was elevated in plasma (and in thrombus) post-IVC occlusion from ICI-treated mice compared to that of IgG-treated mice. Conclusions ICI treatment of tumor-bearing mice undergoing flow restriction-induced thrombosis resulted in enhanced clot formation. Larger thrombi in ICI treated mice was accompanied with enhanced contact activation and NETosis marker CitH3. Figure 1 Figure 1. Disclosures Khorana: Halozyme: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Anthos: Consultancy, Honoraria. McCrae: Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy; Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria.

scholarly journals Thrombotic Complications Associated with Immune Checkpoint Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4606
Author(s):  
Tzu-Fei Wang ◽  
Alok A. Khorana ◽  
Marc Carrier
Keyword(s):  
Immune Checkpoint ◽  
Arterial Thrombosis ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Relevant Information ◽  
Anticancer Treatment ◽  
Thrombotic Complications ◽  
Associated Risk Factors ◽  
Cancer Associated Thrombosis

Thromboembolism is a common complication in patients with cancer and is associated with significant morbidity and mortality. Anticancer treatment is a known risk factor of cancer-associated thrombosis. Immune checkpoint inhibitors have become a mainstay of treatment in various cancers. Both venous and arterial thrombosis have been increasingly reported as adverse events associated with immune checkpoint inhibitors in recent studies, with a cumulative incidence of venous thrombosis to be 5–8% at 6 months and over 10% at 12 months. Additionally, rates of approximately 1–5% for arterial thrombosis were reported at 12 months. Data also showed an association of thromboembolism with adverse survival. Many pertinent clinical questions in this population deserve further investigation, including the risks of thrombosis associated with immune checkpoint inhibitors as compared to those with traditional systemic therapy, associated risk factors, and the optimal prevention and treatment strategies. In this review, we synthesize data from available literature, provide relevant information for clinicians and potential future directions for research.

scholarly journals Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors

2019 ◽  
Vol 38 (4) ◽  
pp. 1200-1206 ◽  
Author(s):  
Yosuke Ando ◽  
Takahiro Hayashi ◽  
Reiko Sugimoto ◽  
Seira Nishibe ◽  
Kaori Ito ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Heart Disease ◽  
Anticancer Agents ◽  
Immune Checkpoint ◽  
Odds Ratio ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
History Of ◽  
Cancer Associated Thrombosis

SummaryPurpose Anticancer agents are known to increase cancer-associated thrombosis (CAT) onset. CAT onset rate is reported to be 1.92% in cisplatin-based therapy, 6.1% in paclitaxel plus ramucirumab combination therapy, and 11.9% in bevacizumab monotherapy. Because immune checkpoint inhibitors (ICIs) cause a sudden increase in T cell number, an association between administration of these drugs and increase in CAT incidence is likely. However, the extent to which ICI administration affects CAT incidence remains unclear. Further, risk factors for CAT incidence have not yet been identified. The present study investigated CAT incidence and associated risk factors in patients receiving ICI. Methods Patients administered nivolumab or pembrolizumab at Fujita Health University Hospital from April 2017 to March 2018 were enrolled. We collected retrospective data regarding age, sex, cancer type, BMI, medical history, laboratory data at treatment initiation, medications, and computed tomography (CT) interpretations from electronic medical records. Results We identified 122 eligible participants from 135 patients receiving nivolumab or pembrolizumab. Ten patients (8.2%) developed CAT. A history of venous thromboembolism (VTE) or arterial thromboembolism (ATE) was a risk factor for CAT incidence (odds ratio: 6.36, P = 0.039). A history of heart disease may be a risk factor for CAT incidence (odds ratio 6.56, P = 0.052). Significantly higher usage of antiplatelet and anticoagulant therapy was noted in patients who developed CAT (60%) than in those who did not (13.4%, p < 0.01). Conclusion High (8.2%) CAT incidence during ICI administration suggested that ICI is not associated with a lower blood clot risk than other anticancer agents investigated in previous studies. For patients with VTE, ATE, or heart disease history, it is crucial to consider the possibility of CAT even with antiplatelet therapy.

Cancer-Associated Thrombosis: Cancer Cell-Derived Microparticles As a Trigger of Venous Thrombosis in a Mouse Model of Flow Restriction

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 34-34
Author(s):  
Grace M. Thomas ◽  
Alexander Brill ◽  
Denisa D. Wagner
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Venous Thrombosis ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Flow Restriction ◽  
Tumor Bearing ◽  
Pancreatic Cancer Cells ◽  
Venous Thromboembolic Events ◽  
Cancer Associated Thrombosis

Abstract Abstract 34 Thrombotic complications are common side effects in cancer patients and up to 20% of all symptomatic cases of deep vein thrombosis (DVT) are thought to be cancer-related. Since Armand Trousseau established a direct correlation between thrombophlebitis and cancer in 1865, cancer-associated thrombosis has been the focus of several studies. All tumor types are associated with thrombosis but the incidence is particularly high (up to 57%) in patients suffering from pancreatic cancer (Sack et al Medicine 1977; Blom et al Eur J Cancer 2006; Cronin-Fenton et al Br J Cancer 2010). Cancer cells shed procoagulant microparticles (MPs) that can reach the bloodstream of pancreatic tumor-bearing mice and of patients with pancreatic cancer (Thomas et al J Exp Med 2009, Zwicker et al Thromb Res 2009). At their surface, these vesicles express a higher density of active tissue factor (TF) when compared to their parental cell (> 100-fold), and were shown to contribute to vessel injury-induced thrombosis (Thomas et al J Exp Med 2009). Furthermore, the concentration of circulating TF-bearing tumor-derived MPs has been correlated with cancer-associated venous thromboembolic events in patients (Del Conde et al J Thromb Haem 2007; Hron et al Thromb Haemost 2007; Langer et al Ann Hematol 2008; Zwicker et al Thromb Res 2009). In this study, we addressed experimentally whether circulating tumor microparticles play a role in DVT associated with cancer. We used a mouse model of DVT where thrombosis is induced by flow restriction (90% reduction in the lumen size) of the inferior vena cava (IVC) (Brill et al Blood 2010). In contrast to most DVT models, this model maintains blood flow in the IVC and it does not induce injury or endothelial denudation and thus is suitable for comparisons to human patients. The DVT model was used in combination with a model of murine pancreatic cancer (Thomas et al J Exp Med 2009). We observed that all the mice implanted subcutaneously with pancreatic cancer cells (Panc02 cell line) and submitted 35 days later to partial flow restriction of the IVC (n=8) developed an occlusive thrombus after 3 hours of flow restriction, while only 2 out of 7 control mice did (P < 0.05). We observed in this DVT model that mice infused with cancer cell-derived MPs have the same phenotype as the tumor-bearing mice since 100% of them developed a thrombus (P < 0.05 when compared to control mice), indicating that circulating tumoral microparticles play an important part in the triggering of cancer-associated DVT. A pro-thrombotic effect could be observed as early as 1 hour after stenosis in cancer cell-derived MPs-injected mice (P < 0.05 when compared to control mice). Moreover, thrombus formation after 1 hour of stenosis could be abolished when mice were pretreated with hirudin, suggesting the importance of the MP-generated thrombin likely by MP-derived TF activity. In conclusion, our results support the hypothesis that tumoral microparticles trigger cancer-associated venous thrombosis. Thus targeting their recruitment or activity could help to prevent cancer-associated DVT and its complication, pulmonary embolism. Disclosures: No relevant conflicts of interest to declare.

646 Evaluating a preclinical model of contact hypersensitivity for skin immune checkpoint toxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A683-A683
Author(s):  
Barbara Ma ◽  
Abhinav Jaiswal ◽  
K Sanjana Devi ◽  
Qingrong Huang ◽  
Joy Hsu ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Clin Oncol ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Contact Hypersensitivity

BackgroundImmune checkpoint inhibitors (ICIs) are limited by the high incidence of immune-related adverse events (irAEs) occurring in up to 40% of solid tumor patients on anti-PD-1 monotherapy 1 2 and 72% in anti-CTLA-4/anti-PD-1 combination.3 4 These toxicities can cause treatment cessation, hospitalization and even death.5–7 IrAEs are variable in severity, timing, onset, and remain poorly understood. Amongst the different toxicities, skin irAEs are most frequent, occur the earliest, and are correlated with a positive prognosis.4 8 However, there is a lack of preclinical models to study checkpoint toxicity. We evaluated a murine model of allergic contact dermatitis (contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8+ T cells to gain a mechanistic understanding of skin checkpoint toxicity.MethodsC57BL/6 mice (n = 5 per group) were sensitized epicutaneously on shaved flank with hapten 0.5% DNFB on day -5 and elicited on their ears with DNFB on day 0. Starting four weeks later, mice were treated with either anti-programmed cell death protein (PD-1) or isotype. At the time of the first recall challenge only, mice were given either anti-PD-1 or isotype. Mice received subsequent rechallenges with DNFB to the ears and ear swelling was measured at various time points. Mice were depleted of circulating or skin CD8+ T cells by anti-CD8 mAbs from day 29 onwards, and maintained weekly, as in this model CD8+ T cells are the main hapten responder population. Samples were collected for histochemistry and analyzed by flow cytometry.ResultsOur data indicate that despite the depletion of circulating T cells, anti-PD-1 recipients mount a higher initial recall response to contact agents. Higher ear swelling was observed with increased inflammation in these mice. Our data suggest anti-PD-1 can liberate local T cell responses in the absence of a contribution from blood, and may offer a model to test therapeutic interventions to alleviate peripheral immune toxicities.ConclusionsOur results suggest that this murine model of contact hypersensitivity represents a potential model for skin immune checkpoint toxicities. This model of locally-mediated inflammatory recall may advance the goal of uncoupling toxicity from efficacy in patients with immune-related adverse events.Ethics ApprovalThe animal study was approved by Weill Cornell Medicine’s IACUC; approval number D16-00186.ReferencesNaidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015;26(12):2375–91. doi: 10.1093/annonc/mdv383.Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016;60:12–25. doi: 10.1016/j.ejca.2016.02.010.Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018;378(2):158–168. doi: 10.1056/NEJMra1703481.Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16(9):563–580. doi: 10.1038/s41571-019-0218-0.Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5(1):95. doi: 10.1186/s40425-017-0300-z.Wills B, Brahmer JR, Naidoo J. Treatment of complications from immune checkpoint inhibition in patients with lung cancer. Curr Treat Options Oncol 2018;19(9):46. doi: 10.1007/s11864-018-0562-9.Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139–148. doi: 10.1016/j.ejca.2015.11.016.Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol 2019:JCO1802141. doi: 10.1200/JCO.18.02141.

A novel dual inhibitor of IDO and TDO, CMG017, potently suppresses the kynurenine pathway and overcomes resistance to immune checkpoint inhibitors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14228-e14228 ◽  
Author(s):  
Chan Kim ◽  
Joo Hoon Kim ◽  
Jin Sung Kim ◽  
Hong Jae Chon ◽  
Joo-Hang Kim
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Suppression ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Kynurenine Pathway ◽  
Dual Inhibitor ◽  
Tumor Bearing

e14228 Background: Kynurenine production by indoleamine 2,3-dioxygenase (IDO) is critical for tumor immune suppression through effector T cell anergy and regulatory T cell proliferation. This has led to the rapid development of IDO inhibitors for cancer immunotherapy. However, results from recent clinical trials have been disappointing and this is partly due to pathway redundancy. Tryptophan 2,3-dioxygenase (TDO), another important enzyme of the kynurenine pathway, plays a compensatory role in the absence of IDO activity. Therefore, we developed a dual inhibitor of IDO and TDO to achieve maximal inhibition of the kynurenine pathway and alleviate tumor immune suppression. Methods: Small-molecule inhibitors of IDO and TDO were synthesized and evaluated using in vitro cell-based assays. Pharmacokinetic and pharmacodynamic profiles were assessed for these inhibitors. Tumor-bearing mice were treated with CMG017 per os, either alone or in combination with immune checkpoint inhibitors (ICIs). The tumor microenvironment (TME) was assessed through histological, flow-cytometric, and Nanostring immune profiling analyses. Results: CMG017 suppressed kynurenine production more effectively than inhibitors targeting either IDO or TDO alone, in various human and murine cancer cell lines. Single administration of CMG017 showed favorable pharmacokinetic profiles compared with an IDO1 selective inhibitor. Repeated once-daily per os administration of CMG017 decreased kynurenine concentration in both tumors and plasma of tumor-bearing mice and delayed tumor growth without significant toxicity. CMG017 induced dramatic changes in immune-related genes in TME and enhanced intratumoral infiltration of CD8+ effector T cells. The anti-tumor activity of CMG017 was almost negated when T cells were depleted, indicating the importance of adaptive immunity for the in vivo efficacy of CMG017. Of note, combination immunotherapy of CMG017 with ICIs (anti-PD-1 and anti-CTLA-4) led to durable tumor regression and long-term overall survival. Mice with complete tumor regression were immune to tumor re-challenge, indicating the establishment of immunological memory. Conclusions: CMG017, a dual inhibitor of IDO and TDO, potently suppressed the kynurenine pathway and showed promising anti-cancer efficacy, with favorable pharmacologic profiles.

scholarly journals 991. Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Mortality, Infection Severity, and Fungal Clearance in an Immunosuppressed Murine Model of Invasive Pulmonary Mucormycosis

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S586-S586
Author(s):  
Sebastian Wurster ◽  
Nathaniel D Albert ◽  
Dimitrios P Kontoyiannis
Keyword(s):  
Murine Model ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Panel Member ◽  
Severe Infection ◽  
Therapeutic Benefit ◽  
Fungal Burden ◽  
Isotype Control ◽  
Pulmonary Mucormycosis ◽  
Checkpoint Pathway

Abstract Background Emerging experimental evidence suggests that immune checkpoint inhibitors (ICIs) enhance antifungal immunity. In addition, there is anecdotal evidence of potential benefit of adjunct PD-1 pathway blockade in patients with intractable mucormycosis. However, proof-of-concept data in animal models are lacking. Therefore, we compared the efficacy of PD-1 and PD-L1 inhibition in an immunosuppressed murine model of invasive pulmonary mucormycosis (IPM). Methods Female 8-9-week-old BALB/c mice were immunosuppressed with cyclophosphamide (150 mg/kg on days -4 and -1, 100 mg/kg on day +3) and cortisone acetate (300 mg/kg on day -1) and infected intranasally with 50,000 Rhizopus arrhizus spores (clinical isolate Ra-749, day 0). On days 0, +2, +4, and +6, mice received intraperitoneal injections of 250 µg/kg PD-1 or PD-L1 blocking antibodies versus (vs.) 250 µg/kg of the corresponding isotype antibodies (all antibodies from Leinco Technologies). Survival was monitored for 7 days post-infection. Infection severity was scored using the murine sepsis score (MSS, 0 = healthy to 3 = moribund). Fungal burden in lung tissue was determined by an 18S quantitative PCR assay on day +7 or upon death. 20 mice per treatment were assessed in 2 independent experiments. Results Control mice with IPM receiving either of the unspecific isotype antibodies developed severe infection (median MSS on day 7, 2.5-3.0) and had a high 7-day mortality (50-55%). Compared to the corresponding isotype control, PD-L1 inhibition provided a strong therapeutic benefit, significantly improving morbidity (median MSS = 1.0 vs. 2.5, p = 0.002), 7-day mortality (15% vs. 50%, p = 0.02), and fungal burden (3.6k vs. 27.2k spore equivalents/lung, p &lt; 0.001). In contrast, blockade of-PD-1 modestly yet non-significantly reduced infection severity (median MSS = 2.1 vs. 3.0, p = 0.48), 7-day mortality (35% vs, 55%, p = 0.12), and fungal burden (5.6k vs. 40.7k spore equivalents/lung, p = 0.09) compared to isotype control. Conclusion Even without concomitant antifungals, blockade of PD-L1 and to a lesser extent of PD-1 improved mortality, infection severity, and fungal clearance in immunosuppressed mice with IPM. Immune phenotyping studies are in progress to better understand the protective antifungal activity of ICIs in IPM. Disclosures Dimitrios P. Kontoyiannis, MD, Astellas (Consultant)Cidara Therapeutics (Advisor or Review Panel member)Gilead Sciences (Consultant, Grant/Research Support, Other Financial or Material Support, Honoraria)

scholarly journals Activation of CD8 T cells accelerates anti-PD-1 antibody-induced psoriasis-like dermatitis through IL-6

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ryota Tanaka ◽  
Yuki Ichimura ◽  
Noriko Kubota ◽  
Akimasa Saito ◽  
Yoshiyuki Nakamura ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Skin Inflammation ◽  
Programmed Cell Death 1

Abstract Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis.

Sunitinib inhibits PD-L1 expression in osteosarcoma by targeting STAT3 and remodels the immune system in tumor-bearing mice

2020 ◽  
Author(s):  
Xian Liang Duan ◽  
Jian Ping Guo ◽  
Fan Li ◽  
Chao Xiu ◽  
Hua Wang
Keyword(s):  
Immune System ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Migration And Invasion ◽  
Osteosarcoma Cells ◽  
Tumor Bearing

Aim: Exploring the mechanisms of the combination therapy using VEGFR-TKI and immune checkpoint inhibitors might be useful to control the development of osteosarcoma. Materials & methods: The expression of PD-L1 and STAT3 in osteosarcoma were determined with western blot. Proliferation, migration and invasion were determined with CCK-8 and Transwell assays. Lung metastases, tumor growth, survival and immune cell populations were performed in tumor-bearing mice. Results: Sunitinib reduced the expression of PD-L1 by inhibiting the activation of STAT3 and suppressed the migration and invasion in osteosarcoma cells. Combination therapy reduced lung metastases, tumor growth, improved survival and reverse tumor microenvironment in tumor-bearing mice. Conclusion: Sunitinib inhibits PD-L1 expression by targeting STAT3 and remodels the immune system in tumor-bearing mice.

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