Abstract:
:The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.
journal_name
Oncoimmunologyjournal_title
Oncoimmunologyauthors
Ekiz HA,Lai SA,Gundlapalli H,Haroun F,Williams MA,Welm ALdoi
10.1080/2162402X.2018.1480286subject
Has Abstractpub_date
2018-07-11 00:00:00pages
e1480286issue
9eissn
2162-4011issn
2162-402Xpii
1480286journal_volume
7pub_type
杂志文章相关文献
OncoImmunology文献大全abstract::To antagonize tumor-derived TGFβ contemporaneously to anticancer immunotherapy, we genetically engineered a fusion protein coupling IL-2 and the ectodomain of TGFβ receptor II (Fusion of Interleukin-2 and Soluble TGFβ receptor - a.k.a. FIST). FIST possesses intriguing gain-of-function properties and induces potent act...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.1.2.18458
更新日期:2012-03-01 00:00:00
abstract::Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct nega...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2016.1226720
更新日期:2016-09-09 00:00:00
abstract::Immune responses to tumor antigens have been reported in cancer patients. However, the relevance of such spontaneous immune responses to the clinical course has not been studied extensively. We showed that the overall survival of patients with antibodies against NY-ESO-1 or XAGE1 (GAGED2a) antigen was prolonged in gas...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/21624011.2014.970032
更新日期:2014-12-21 00:00:00
abstract:: Background : Peritoneal carcinomatosis (PC) is a terminal evolution from primary colorectal cancer (pCRC) associated with poor patient survival. Impact of the immune cell infiltrate on PC pathogenesis is unknown. Therefore, we characterized the immunological tumor microenv...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2016.1242543
更新日期:2016-10-14 00:00:00
abstract::The elicitation of efficient antitumor immune responses requires the optimal activation of tumor-associated dendritic cells (DCs). Our comparison of the effect of various immunostimulatory treatments on DCs revealed that the best predictor of the success of immunotherapy is not the activation of existing DC population...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.26443
更新日期:2013-11-01 00:00:00
abstract::Programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have shown activity in patients with advanced renal cell carcinoma (RCC). However, the role of PD-1 expression in tumor-infiltrating lymphocytes (TILs) as a biomarker for poor outcome is not clear. In this study, we evaluated the prognostic value of T...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2017.1413519
更新日期:2018-01-10 00:00:00
abstract::We have recently described two types of Langerhans cells (LCs), which develop via separate pathways in steady-state conditions and during inflammation. Here, we propose that these two types of LCs differ in their requirement for transforming growth factor β1 (TGFβ1), and we discuss how TGFβ1 impacts on the development...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.23083
更新日期:2013-03-01 00:00:00
abstract::In hepatocellular carcinoma (HCC) patients, the intratumoral expression of Toll-like receptor-3 (TLR3) correlates with prolonged survival. We demonstrated that TLR3 ligands can operate through three independent mechanisms: by directly killing TLR3-expressing cancer cells, by inducing T- and natural killer (NK)-cell in...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.23493
更新日期:2013-04-01 00:00:00
abstract::The B7 family and tumor necrosis factor receptor (TNFR) superfamily play a vital role in the T-cell co-stimulatory and co-inhibitory pathways, regulating T-cell activation, tolerance, and exhaustion; therapeutic modulation of these pathways is translated into effective new cancer treatments. Better understanding of th...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2017.1288329
更新日期:2017-02-16 00:00:00
abstract::Alkylating chemotherapy exerts both antineoplastic and immunostimulatory effects. However, in addition to depleting regulatory T cells (Treg), alkylating agents also mediate a long lasting antiproliferative effect on responder lymphocytes. Our recent findings indicate that this antiproliferative effect profoundly impa...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.26294
更新日期:2013-10-01 00:00:00
abstract::Although invariant natural killer T (iNKT) cells influence antitumor responses indirectly by secreting cytokines and promoting the cytolytic functions of T and NK cells, we find that iNKT cells mediate direct tumoricidal activity in vitro and significantly inhibit tumor growth in vivo, even in the absence of other cyt...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.27440
更新日期:2013-12-01 00:00:00
abstract::Human papillomavirus (HPV) infection is one of the most important etiologic causes of oropharyngeal head and neck squamous cell carcinoma (HNSCC). Patients with HPV-positive HNSCC were reported to have a better clinical outcome than patients with HPV-negative cancers. However, little is known about the possible causes...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/21624011.2014.965570
更新日期:2015-01-30 00:00:00
abstract::Both genetic and environmental factors are thought to be causal in gliomagenesis. Several genes have been implicated in glioma development, but the putative role of a major immunity-related gene complex member, immunoglobulin heavy chain γ (IGHG) has not been evaluated. Prior observations that IGHG-encoded γ marker (G...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.28609
更新日期:2014-05-23 00:00:00
abstract::Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. How...
journal_title:Oncoimmunology
pub_type: 杂志文章,评审
doi:10.1080/2162402X.2017.1338237
更新日期:2017-08-31 00:00:00
abstract::The efficacy of antitumoral responses can be increased using combinatorial vaccine strategies. We recently showed that vaccination could be optimized by local administration of diverse molecular or bacterial agents to target and augment antitumoral CD8 T cells in the genital mucosa (GM) and increase regression of cerv...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2015.1016697
更新日期:2015-05-22 00:00:00
abstract::DNA vaccines are potential tools for the induction of immune responses against both infectious disease and cancer. The dermal application of DNA vaccines is of particular interest since the epidermal and dermal layers of the skin are characterized by an abundance of antigen-presenting cells (APCs). The aim of our stud...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.22563
更新日期:2012-12-01 00:00:00
abstract::Three recent publications identified the TNF/TNR2 pathway as a new target to reduce graft-versus-host-disease through regulatory T cells activation or to potentially switch on a strong anti-leukemic effect through regulatory T cells blockade in allogeneic hematopoietic stem cell transplantation. This identified the TN...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2017.1373236
更新日期:2017-09-21 00:00:00
abstract::Aberrantly glycosylated tumor antigens represent promising targets for the development of anti-cancer vaccines, yet how glycans influence immune responses is poorly understood. Recent studies have demonstrated that GalNAc-glycosylation enhances antigen uptake by dendritic cells as well as CD4+ T-cell and humoral respo...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.23659
更新日期:2013-04-01 00:00:00
abstract::The potential of a tumor cell to metastasize profoundly depends on its microenvironment, or "niche" interactions with local components. Tumor-associated-macrophages (TAMs) are the most abundant subpopulation of tumor stroma and represent a key component of tumor microenvironment. The dynamic interaction of cancer cell...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2016.1196299
更新日期:2016-07-15 00:00:00
abstract::Removing less potent T cell subsets as well as poorly- or non-engineered cells can optimize effectiveness of engineered T cell therapy against cancer. We have recently described a novel, GMP-ready method for the purification of engineered immune cells that might further boost the clinical success of cancer immunothera...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2015.1076608
更新日期:2015-08-27 00:00:00
abstract::Successful cancer immunotherapy is thought to require de novo priming of tumor specific CD8(+) T cells in lymphatic organs. Contrasting these beliefs, cancer therapy based on interleukin-10 (IL-10) results in tumor rejection without a requirement for T-cell trafficking from lymphatic organs. Rather, IL-10 directly act...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.21683
更新日期:2012-12-01 00:00:00
abstract::We have made major advances in the treatment of melanoma through the use of targeted therapy and immune checkpoint blockade; however, clinicians are posed with therapeutic dilemmas regarding timing and sequence of therapy. There is a growing appreciation of the impact of antitumor immune responses to these therapies, ...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2015.1136044
更新日期:2016-02-02 00:00:00
abstract::Immune suppression is recognized as a hallmark of cancer and this notion is largely based on studies on cellular immunity. Our recent studies have demonstrated a potential new mechanism of cancer suppression of immunity by impairment of antibody effector function mediated by proteolytic enzymes in the tumor microenvir...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2015.1122861
更新日期:2015-12-29 00:00:00
abstract::Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated p...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2017.1320009
更新日期:2017-04-20 00:00:00
abstract::The alarmin IL-33 is an IL-1 family member that stimulates pleiotropic immune reactions depending on the target tissue and microenvironmental factors. In this study, we have investigated the role of IL-33/ST2 axis in antitumor response to melanoma. Injection of IL-33 in mice-bearing subcutaneous B16.F10 melanoma resul...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2017.1317420
更新日期:2017-04-20 00:00:00
abstract::Lung-specific overexpression of prostacyclin synthase (PGIS) decreases tumor initiation in murine lung cancer models. Prostacyclin analogs prevent lung tumor formation in mice and reverse bronchial dysplasia in former smokers. However, the effect of prostacyclin on lung cancer progression has not been well studied. We...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2017.1423182
更新日期:2018-02-13 00:00:00
abstract::The functional status of CD4(+) T cells is a critical determinant of antitumor immunity. Polyfunctional CD4(+) T cells possess the ability to concomitantly produce multiple Th1-type cytokines, exhibiting a functional attribute desirable for cancer immunotherapy. However, the mechanisms by which these cells are induced...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2016.1171445
更新日期:2016-04-25 00:00:00
abstract::Efficient immunotherapy relies on the rapid generation of elevated amounts of cancer-specific T lymphocytes. We have recently demonstrated that both rapid and potent tumor-targeting immune responses can be induced with a heterologous prime-boost regimen consisting of poly-lactic co-glycolic acid (PLGA) microsphere-bas...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.4161/onci.27873
更新日期:2014-02-14 00:00:00
abstract::Despite the opposite roles of Tbet and Foxp3 in the immune system as well as in tumour biology, recent studies have demonstrated the presence of of CD4+ T cells, expressing both, Tbet and Foxp3. Although Tbet+Foxp3+ T cells are currently a subject of intense research, less is known about their biological function espe...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2018.1456612
更新日期:2018-04-25 00:00:00
abstract::We have shown that melanoma-derived factors alter the function of differentiated tissue-resident dendritic cells (DC) in a tumorigenicity-dependent manner. Soluble factors, including TGFβ1 and VEGF-A, contributed to dendritic cell dysfunction associated with a highly-aggressive melanoma and conferred a phenotype upon ...
journal_title:Oncoimmunology
pub_type: 杂志文章
doi:10.1080/2162402X.2015.1069462
更新日期:2015-08-12 00:00:00