scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1+ triple negative breast cancer cells

06 Jun 2019-OncoImmunology (Taylor & Francis)-Vol. 8, Iss: 9
TL;DR: It is shown that FDA-approved anti-PD-L1 antibody, atezolizumab (ATE), potentiates T cell-mediated cytotoxicity and apoptosis of TNBC cells that express higher levels of PD-L 1, but does not have significant effect on T NBC cells expressing low levels ofPD- L1.
Abstract: Immune check point inhibitors targeting programmed cell death protein-1 (PD-1) and its ligand (PD-L1) have shown clinical success in treatment of human malignancies. Triple negative breast cancer (TNBC), which is primarily characterized by high heterogeneity and presence of tumor infiltrating lymphocytes, remains therapeutic challenge due to unavailability of approved targeted therapy. Therapeutic potential of immune check point inhibitors for TNBC patients is under active clinical investigation. In this study, we show that FDA-approved anti-PD-L1 antibody, atezolizumab (ATE), potentiates T cell-mediated cytotoxicity and apoptosis of TNBC cells that express higher levels of PD-L1, but does not have significant effect on TNBC cells expressing low levels of PD-L1. PD-L1 knockdown further confirmed that ability of ATE to promote T cell-induced cytotoxicity is PD-L1 expression dependent. Combination of ATE with PD-L1 upregulating agents, such as HDAC, proteasomal, and lysosomal inhibitors, further augmented cytotoxic activity of T cells toward TNBC cells. Based on analysis of breast cancer tissue samples deposited in The Cancer Genome Atlas (TCGA), we found a positive correlation between PD-L1 and focal adhesion kinase (FAK) mRNA expression in PD-L1-positive (PD-L1+) TNBC, suggesting a functional association of FAK and immune checkpoints. We further demonstrate that ATE dramatically downregulates phosphorylation status of FAK, an important regulator of cell invasion and migration, and significantly enhances FAK inhibitor mediated inhibition of cell motility and invasion of PD-L1+ TNBC cells independent of T cells. Taken together, our data suggest that ATE shows promising anti-tumor activity in PD-L1+ TNBC via both T cell-dependent and -independent mechanisms.
Citations
More filters
01 Jan 2014
TL;DR: In this article, the authors validate the prognostic impact of tumor-infiltrating lymphocytes (TILs) in primary triple-negative breast cancer (TNBC) in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG).
Abstract: Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

719 citations

Journal ArticleDOI
TL;DR: An overview of recent developments in immunotherapy is given and a new direction of tumor treatment is indicated through analyzing the pros and cons of immunotherapy coupled with keeping a close watch on the development trend of the immunotherapy future.

251 citations

Journal ArticleDOI
TL;DR: The role of nuclear FAK as a driver for tumor cell survival as well as potential therapeutic strategies to target FAK in both tumors and the TME are discussed.
Abstract: Focal adhesion kinase (FAK) is an integrin-associated protein tyrosine kinase that is frequently overexpressed in advanced human cancers. Recent studies have demonstrated that aside from FAK's catalytic activity in cancer cells, its cellular localization is also critical for regulating the transcription of chemokines that promote a favorable tumor microenvironment (TME) by suppressing destructive host immunity. In addition to the protumor roles of FAK in cancer cells, FAK activity within cells of the TME may also support tumor growth and metastasis through various mechanisms, including increased angiogenesis and vascular permeability and effects related to fibrosis in the stroma. Small molecule FAK inhibitors have demonstrated efficacy in alleviating tumor growth and metastasis, and some are currently in clinical development phases. However, several preclinical trials have shown increased benefits from dual therapies using FAK inhibitors in combination with other chemotherapies or with immune cell activators. This review will discuss the role of nuclear FAK as a driver for tumor cell survival as well as potential therapeutic strategies to target FAK in both tumors and the TME.

83 citations

Journal ArticleDOI
TL;DR: The mechanisms of the regulation of checkpoint inhibitors (PD-1/PD-L1) in breast cancer are discussed, the predictive aspects in the PD-L 1 testing are explored and the most accurate and reliable assessment of immune cells as potential targets are discussed.

61 citations

Journal ArticleDOI
TL;DR: Preclinical and clinical evidence recently collected are summarized to support the development of resiquimod and motolIMod and other TLR7/TLR8 agonists as anticancer agents.
Abstract: Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and ...

51 citations

References
More filters
Journal ArticleDOI
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

10,602 citations


"Atezolizumab potentiates Tcell-medi..." refers background in this paper

  • ...Immune checkpoints are a set of inhibitory pathways in the immune system that are required for maintaining self-tolerance and preventing host tissue damage by regulating durability of immune response.(7) Programmed cell death ligand 1 (PD-L1), a key immune checkpointmolecule andmember of B7 transmembrane protein family, interacts with its receptor, programmed cell death (PD-1), and induces negative regulatory signal by neutralizing cytotoxic T cell activity....

    [...]

Journal ArticleDOI
TL;DR: It is reported here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1 and the findings have implications for the design of T cell–based cancer immunotherapy.
Abstract: B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-gamma upregulates B7-H1 on the surface of tumor cell lines. Cancer cell-associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1(+) tumors in vivo. These findings have implications for the design of T cell-based cancer immunotherapy.

4,290 citations


"Atezolizumab potentiates Tcell-medi..." refers background in this paper

  • ...Programmed cell death ligand 1 (PD-L1), a key immune checkpointmolecule andmember of B7 transmembrane protein family, interacts with its receptor, programmed cell death (PD-1), and induces negative regulatory signal by neutralizing cytotoxic T cell activity.(8) Early preclinical studies have shown that disrupting PD-L1/PD-1 association by using monoclonal antibodies may enhance anti-tumor immunity and promote tumor regression in in vitro and in vivo models....

    [...]

Journal ArticleDOI
27 Nov 2014-Nature
TL;DR: Evaluated data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment, as well as across multiple cancer types.
Abstract: The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

4,227 citations


"Atezolizumab potentiates Tcell-medi..." refers background in this paper

  • ...ATE, which selectively targets PD-L1 and inhibit binding of PD-L1 to receptor PD-1, showed improved clinical utility against urothelial and non-small cell lung carcinomas, and later received market approval for such patient populations.16,17 ATE, formerly known as MPDL3280A, was isolated from a single phage clone by screening human phage display library directed against extracellular domain-Fc fusion of human PD-L1....

    [...]

  • ...ATE, formerly known as MPDL3280A, was isolated from a single phage clone by screening human phage display library directed against extracellular domain-Fc fusion of human PD-L1.(18) Although clinical activity of ATE is explored in variety of cancer types, more recently, a phase 3 clinical trial using ATE with nabpaclitaxel in patients with locally advanced or metastatic TNBC patients showed significantly longer progression-free survival compared with placebo-nab-paclitaxel treated group....

    [...]

  • ...Previous study has shown that proteasomal inhibitor MG132 can increase PD-L1 expression in prostate cancer cells by blocking its degradation,24 hence we hypothesized that combining ATE with proteasomal and lysosomal inhibitors in immune-dependent cytotoxicity assays can further increase efficacy of ATE against TNBC cells by preventing proteasomal or lysosomal-mediated degradation of PD-L1....

    [...]

Journal ArticleDOI
TL;DR: Gen expression profiles from 21 breast cancer data sets and identified 587 TNBC cases may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
Abstract: Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

4,215 citations


"Atezolizumab potentiates Tcell-medi..." refers background in this paper

  • ...Triple negative breast cancer (TNBC), which represents about 10–20% of all mammary tumors, is characterized by lack of molecular therapeutic targets like estrogen receptor (ER), progesterone receptor (PR) and HER2.(1,2) TNBCs are highly aggressive tumors with dismal prognosis....

    [...]

  • ...Triple negative breast cancer (TNBC), which represents about 10–20% of all mammary tumors, is characterized by lack of molecular therapeutic targets like estrogen receptor (ER), progesterone receptor (PR) and HER2....

    [...]

Journal ArticleDOI
TL;DR: Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations, and overall survival improvement was similar in patients with squamous non-squamous lung cancer.

3,496 citations


"Atezolizumab potentiates Tcell-medi..." refers background in this paper

  • ...ATE, which selectively targets PD-L1 and inhibit binding of PD-L1 to receptor PD-1, showed improved clinical utility against urothelial and non-small cell lung carcinomas, and later received market approval for such patient populations.(16,17) ATE, formerly known as MPDL3280A, was isolated from a single phage clone by screening human phage display library directed against extracellular domain-Fc fusion of human PD-L1....

    [...]