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

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.

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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 ◽

10.1002/cncr.30726 ◽

2017 ◽

Vol 123 (17) ◽

pp. 3291-3304 ◽

Cited By ~ 81

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

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

Journal of Cancer ◽

10.7150/jca.18683 ◽

2017 ◽

Vol 8 (11) ◽

pp. 2018-2025 ◽

Cited By ~ 36

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

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

Oncogene ◽

10.1038/s41388-021-02170-0 ◽

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.

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Multicenter phase II study of pembrolizumab (P) in advanced soft tissue (STS) and bone sarcomas (BS): Final results of SARC028 and biomarker analyses.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11008 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11008-11008 ◽

Cited By ~ 22

Author(s):

Melissa Amber Burgess ◽

Vanessa Bolejack ◽

Brian Andrew Van Tine ◽

Scott Schuetze ◽

James Hu ◽

...

Keyword(s):

T Cell ◽

Phase Ii ◽

Phase Ii Study ◽

Cell Infiltration ◽

Clinical Activity ◽

Multiple Time ◽

Histologic Subtype ◽

T Cell Infiltration ◽

Multicenter Phase

11008 Background: SARC028 is the first multicenter Phase II study of P monotherapy in patients (pts) with STS and BS. Designed to detect clinical efficacy signals in multiple histologies, the study collected blood & tissue samples on all pts. We report extended clinical follow-up and in-depth biomarker correlates of response. Methods: The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints were safety, 12 wk progression-free survival (PFS), and overall survival (OS). The STS arm had 10 pts in each of 4 cohorts: undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), synovial sarcoma (SS) and leiomyosarcoma (LMS). The BS arm included 40 pts with osteosarcoma (OS), Ewing sarcoma (ES) or dedifferentiated chondrosarcoma (CS). Pre- and on-P biopsies were required as well as blood at multiple time points. Tumor was assessed for PD-L1 expression (clone 22C3) and immune infiltrates by multi-color IHC (Vectra). Ongoing analyses include circulating cytokine and checkpoint levels and exome (DNA), transcriptome (RNA), and T-cell receptor (TCR) sequencing. Results: 86 pts were enrolled, 80 were evaluable for response. For STS, median follow-up was 14.5 months. The ORR in the overall STS cohort was 18% and the 12-wk PFS 55% [95% CI, 42-71]). Clinical activity was variable by histologic subtype with 40% ORR in UPS (1 CR and 3PR out of 10 evaluable pts), 2 PR/10 were seen in DDLPS, 1PR/10 in SS and 0/10 in LMS. For BS, median follow-up was 12.3 months (ORR 5%; 12-wk PFS 28% [95% CI, 14-41]), with 1PR/22 OS, 1PR/5 CS and 0/13 ES. 70 pre-P tissues were analyzed (11 excluded for insufficiency), with PD-L1+ in 3/70 (4%); all 3 were UPS. Of the 2 evaluable pts, 1 had CR and 1 PR. 2 OS were PD-L1+ on multi-color IHC, 1 had PR. All PD-L1+ samples had CD8+ T-cell infiltration. There were no post-P PD-L1+ samples. Conclusions: P has clinical activity in UPS and LPS, and expansion cohorts in those subtypes are planned. Pre-treatment PD-L1 expression was infrequent, but correlated with T-cell infiltration and response in UPS & OS. Ongoing biomarker analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT02301039.

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

10.1101/2021.03.11.434711 ◽

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.

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