scholarly journals Propranolol reduces sarcoma growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

2021 ◽  
Author(s):  
Klaire Yixin Fjæstad ◽  
Anne Mette Askehøj Rømer ◽  
Victor Goitea ◽  
Astrid Zedlitz Johansen ◽  
Marie-Louise Thorseth ◽  
...  
Keyword(s):  
T Cell ◽  
Soft Tissue ◽  
Immune Checkpoint Inhibitor ◽  
Soft Tissue Sarcomas ◽  
Suppressor Cells ◽  
European Medicines Agency ◽  
Cancer Cell Proliferation ◽  
T Cell Infiltration ◽  
Propranolol Treatment ◽  
Deficient Mice

AbstractThe nonselective beta blocker, propranolol, which for decades has been prescribed for treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis.Here, we have investigated the anti-angiogenic properties of propranolol in the context of stimulating an anti-tumor immune response. We show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma tumors and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol-treatment leads to an upregulation of PD-L1 on tumor-associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy.Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

scholarly journals Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

Oncogene ◽  
2022 ◽  
Author(s):  
Klaire Yixin Fjæstad ◽  
Anne Mette Askehøj Rømer ◽  
Victor Goitea ◽  
Astrid Zedlitz Johansen ◽  
Marie-Louise Thorseth ◽  
...  
Keyword(s):  
T Cell ◽  
Soft Tissue ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Soft Tissue Sarcomas ◽  
Suppressor Cells ◽  
European Medicines Agency ◽  
Cancer Therapies ◽  
T Cell Infiltration ◽  
Propranolol Treatment

AbstractThe development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

Correlation of T-cell infiltration and clonality with PD-L1 expression in soft tissue sarcomas.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 23-23
Author(s):  
Seth Pollack ◽  
Qianchuan He ◽  
Jennifer Yearley ◽  
Ryan O Emerson ◽  
Marissa Vignali ◽  
...  
Keyword(s):  
T Cell ◽  
Soft Tissue ◽  
Antigen Presentation ◽  
Soft Tissue Sarcomas ◽  
Cell Infiltration ◽  
Strong Immune Response ◽  
Histologic Subtype ◽  
T Cell Infiltration ◽  
Metastatic Setting ◽  
Highly Correlated

23 Background: The success of immunotherapy has raised new issues regarding the selection of patients, design of combination strategies, and sequencing of various regimens. Sarcomas have poor outcomes in the metastatic setting but may be amenable to immune therapies. However, we currently have limited knowledge of the immunologic profiles of different soft tissue sarcoma (STS) subtypes. Methods: We identified patients with the relatively common STS subtypes: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS) and liposarcoma. Formalin fixed paraffin embedded (FFPE) tumor samples from 81 patients underwent gene expression analysis, immunohistochemistry for PD-1 and PD-L1, and sequencing of the T cell receptor Vβ region. Differences in liposarcoma subsets were also evaluated. Results: UPS and LMS had high expression levels of genes related to antigen presentation and T cell infiltration. UPS had higher levels of PD-L1 (p ≤ 0.001) and PD-1 (p ≤ 0.05) on IHC. UPS also had the highest T cell infiltration based on TCR sequencing, significantly more than SS, which had the lowest (p ≤ 0.05). UPS and LMS both had higher clonality compared with SS and liposarcoma (p ≤ 0.05). A model adjusted for STS histologic subtype found that for all sarcoma T cell infiltration and clonality were highly correlated with PD-1 and PD-L1 staining levels (p ≤ 0.01). Conclusions: In a model adjusted for sarcoma histologic subtypes, T cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression, consistent with the emerging view of tumor immunity that highly inflamed tumors acquire inhibitory ligands to evade tumor-specific T cells. UPS, which is a more highly mutated STS subtype, provokes a strong immune response evidenced by multiple inflammatory features suggesting that it may be well-suited to checkpoint inhibitor based approaches. SS and liposarcoma subsets are less highly mutated but do express immunogenic self-antigens therefore strategies to improve antigen presentation and T cell infiltration may be valuable for allowing immunotherapeutic success in these tumor types.

scholarly journals T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas

Cancer ◽  
2017 ◽  
Vol 123 (17) ◽  
pp. 3291-3304 ◽  
Author(s):  
Seth M. Pollack ◽  
Qianchuan He ◽  
Jennifer H. Yearley ◽  
Ryan Emerson ◽  
Marissa Vignali ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Soft Tissue ◽  
Programmed Cell Death ◽  
Soft Tissue Sarcomas ◽  
Cell Infiltration ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death ◽  
Cell Death Protein

scholarly journals Tumor and Peripheral Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3885
Author(s):  
Luana Madalena Sousa ◽  
Jani Sofia Almeida ◽  
Tânia Fortes-Andrade ◽  
Manuel Santos-Rosa ◽  
Paulo Freitas-Tavares ◽  
...  
Keyword(s):  
T Cells ◽  
Soft Tissue ◽  
Cd8 T Cells ◽  
Soft Tissue Sarcomas ◽  
Suppressor Cells ◽  
Response To Therapy ◽  
Immune Checkpoints ◽  
Soluble Factors ◽  
Lymphocyte To Monocyte Ratio ◽  
Immune Related Genes

Soft Tissue Sarcomas (STS) are a heterogeneous and rare group of tumors. Immune cells, soluble factors, and immune checkpoints are key elements of the complex tumor microenvironment. Monitoring these elements could be used to predict the outcome of the disease, the response to therapy, and lead to the development of new immunotherapeutic approaches. Tumor-infiltrating B cells, Natural Killer (NK) cells, tumor-associated neutrophils (TANs), and dendritic cells (DCs) were associated with a better outcome. On the contrary, tumor-associated macrophages (TAMs) were correlated with a poor outcome. The evaluation of peripheral blood immunological status in STS could also be important and is still underexplored. The increased lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR), higher levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and Tim-3 positive CD8 T cells appear to be negative prognostic markers. Meanwhile, NKG2D-positive CD8 T cells were correlated with a better outcome. Some soluble factors, such as cytokines, chemokines, growth factors, and immune checkpoints were associated with the prognosis. Similarly, the expression of immune-related genes in STS was also reviewed. Despite these efforts, only very little is known, and much research is still needed to clarify the role of the immune system in STS.

scholarly journals Targeting pulmonary tumor microenvironment with CXCR4-inhibiting nanocomplex to enhance anti–PD-L1 immunotherapy

2020 ◽  
Vol 6 (20) ◽  
pp. eaaz9240 ◽  
Author(s):  
Zhaoting Li ◽  
Yixin Wang ◽  
Yuexin Shen ◽  
Chenggen Qian ◽  
David Oupicky ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Objective Response ◽  
Suppressor Cells ◽  
Pulmonary Delivery ◽  
Lymphocytic Infiltration ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Cell Accumulation ◽  
Immunosuppressive Cell

Anti–programmed cell death 1 ligand 1 (PD-L1) therapy is extraordinarily effective in select patients with cancer. However, insufficient lymphocytic infiltration, weak T cell–induced inflammation, and immunosuppressive cell accumulation in the tumor microenvironment (TME) may greatly diminish the efficacy. Here, we report development of the FX@HP nanocomplex composed of fluorinated polymerized CXCR4 antagonism (FX) and paclitaxel-loaded human serum albumin (HP) for pulmonary delivery of anti–PD-L1 small interfering RNA (siPD-L1) to treat orthotopic lung tumors. FX@HP induced T cell infiltration, increased expression of calreticulin on tumor cells, and reduced the myeloid-derived suppressor cells/regulatory T cells in the TME, thereby acting synergistically with siPD-L1 for effective immunotherapy. Our work suggests that the CXCR4-inhibiting nanocomplex decreases tumor fibrosis, facilitates T cell infiltration and relieves immunosuppression to modulate the immune process to improve the objective response rate of anti–PD-L1 immunotherapy.

503 Tumor infiltrating lymphocytes in soft tissue sarcomas upregulate the exhaustion marker TIGIT and are reinvigorated by IL-15 stimulation and TIGIT blockade

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A538-A538
Author(s):  
Sean Judge ◽  
Morgan Darrow ◽  
Steven Thorpe ◽  
Alicia Gingrich ◽  
Edmond O’Donnell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Soft Tissue ◽  
Ex Vivo ◽  
Soft Tissue Sarcomas ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
And Function ◽  
Infiltrating Lymphocytes

BackgroundAlthough the presence and activity of tumor infiltrating lymphocytes (TILs) have been shown to be important factors for survival and response to immunotherapy for multiple cancer types, the benefits of immunotherapy in soft tissue sarcomas (STS) have been limited, and novel approaches are needed. In this study, we sought to characterize the phenotype and function of tumor infiltrating natural killer (NK) and T cells in STS patients and to evaluate clinically relevant strategies to augment TIL function.MethodsUsing both prospectively collected blood and tumor tissue from STS patients undergoing surgical resection (n = 21) and archived specimens (n = 45), we performed flow cytometry and immunohistochemistry to evaluate the extent of peripheral and intratumoral CD3-CD56+ NK and CD8+ T cell phenotype and function as predictors of outcome. We also analyzed TCGA data and the peripheral blood of dogs with spontaneous osteosarcoma receiving inhaled IL-15 on a clinical trial to evaluate the association of CD3-NKp46+ NK and CD8+ T cell activation as well as TIGIT upregulation with outcome. Finally, we stimulated patient PBMCs and TILs ex vivo with IL-15 and a novel human anti-TIGIT antibody to assess the impact of combination therapy on NK and T cell phenotype and function. Parametric and non-parametric statistical tests were used where appropriate. Univariate and multivariate survival analyses were performed by Cox proportional hazards models.ResultsCompared to peripheral expression, intratumoral NK and T cells showed an activated and exhausted phenotype by CD69 and TIGIT, respectively. Ex vivo TIL stimulation with IL-15 further increased markers of activation and function including CD69, Ki67, IFNg, and granzyme B, while increasing expression of exhaustion marker TIGIT. Analysis of a retrospective STS cohort and TCGA STS gene expression confirmed the association of TILs with improved prognosis. Dogs with metastatic osteosarcoma receiving inhaled IL-15 exhibited upregulation of activation markers and TIGIT. In vitro, IL-15 and TIGIT blockade of both peripheral and intratumoral NK cells increased cytotoxicity against sarcoma cell lines and increased expression of degranulation marker CD107a compared to IL-15 alone.ConclusionsTILs are associated with improved survival in STS, and tumor infiltrating NK and T cells show features of both increased activation and increased exhaustion. Tumor-infiltrating NK and T cells respond to IL-15 stimulation, but simultaneously further upregulate TIGIT with the combination of IL-15 and TIGIT blockade showing greatest cytotoxic effects. Overall, our data suggest that the combination of IL-15 and TIGIT blockade is a promising clinical strategy in STS.Ethics ApprovalAll experiments involving human and canine patients were approved by the respective Institutional Review Boards at the University of California, Davis, Schools of Medicine (Protocol #218204-9) and Veterinary Medicine (IACUC #20179).

scholarly journals Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhaohan Wei ◽  
Xiaoqiong Zhang ◽  
Tuying Yong ◽  
Nana Bie ◽  
Guiting Zhan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Therapy ◽  
Suppressor Cells ◽  
Long Term Memory ◽  
Tumor Resistance ◽  
Anticancer Efficacy ◽  
T Cell Infiltration ◽  
Tumor Accumulation ◽  
Immunosuppressive Microenvironment

AbstractThe main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8+ T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8+ T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.

scholarly journals PD-L1 Expression Is Associated with FOXP3+ Regulatory T-Cell Infiltration of Soft Tissue Sarcoma and Poor Patient Prognosis

2017 ◽  
Vol 8 (11) ◽  
pp. 2018-2025 ◽  
Author(s):  
Yi Que ◽  
Wei Xiao ◽  
Yuan-xiang Guan ◽  
Yao Liang ◽  
Shu-mei Yan ◽  
...  
Keyword(s):  
T Cell ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Regulatory T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Poor Patient ◽  
Patient Prognosis

scholarly journals Expansion of Myeloid Suppressor Cells in SHIP-Deficient Mice Represses Allogeneic T Cell Responses

2004 ◽  
Vol 173 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
Tomar Ghansah ◽  
Kim H. T. Paraiso ◽  
Steven Highfill ◽  
Caroline Desponts ◽  
Sarah May ◽  
...  
Keyword(s):  
T Cell ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Suppressor Cells ◽  
Cell Responses ◽  
Deficient Mice

scholarly journals Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma

2020 ◽  
Vol 8 (2) ◽  
pp. e001435
Author(s):  
Kohei Shigeta ◽  
Aya Matsui ◽  
Hiroto Kikuchi ◽  
Sebastian Klein ◽  
Emilie Mamessier ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Combination Therapy ◽  
Tumor Vasculature ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Pd1 Blockade ◽  
Endothelial Growth Factor ◽  
Deficient Mice

Background and purposeCombining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.Basic proceduresWe used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.Main findingsRegorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10—a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes—in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.Principal conclusionsJudicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

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