Human IP10-scFv and DC-induced CTL synergistically inhibit the growth of glioma in a xenograft model

Wang, Xuan; Zhang, Fangcheng; Zhao, Hongyang; Lü, Xiaoling; Sun, Yun; Zhang, Xiong; Jiang, Xiaobing

doi:10.1007/s13277-014-1867-3

Cited by 19 publications

(20 citation statements)

References 49 publications

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“…This analysis showed that CXCL9 production was significantly induced in an IFNg-dependent manner following therapy both at the transcriptional and protein level and that the production of CXCR3 ligands was critical for therapeutic efficacy. The requirement for the CXCL9:CXCR3 axis for the therapeutic efficacy of these immunotherapeutic treatments is consistent with previous data indicating that CXCL9/CXCL10:CXCR3 interactions govern immune cell infiltration into tumors prior to therapy (47) and following chemotherapy (10,48,49), IL2 treatment (50,51), adoptive cellular therapy (12,52,53), bispecific antibodies (54), and that CXCR3 À/À mice fail to elicit effective antitumor immune responses postvaccination and anti-PD-1 (55). These studies have shown that CXCL9 and CXCL10 can modulate antitumor immune responses evoked following several therapeutic approaches.…”

Section: Discussionsupporting

confidence: 89%

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

House

Savas

Lai

et al. 2020

Clinical Cancer Research

422

320

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Purpose: Response rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with the extent of tumor immune infiltrate, but the mechanisms underlying the recruitment of T cells following therapy are poorly characterized. A greater understanding of these processes may see the development of therapeutic interventions that enhance T-cell recruitment and, consequently, improved patient outcomes. We therefore investigated the chemokines essential for immune cell recruitment and subsequent therapeutic efficacy of these immunotherapies. Experimental Design: The chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using NanoStringbased analysis with results confirmed at the protein level by flow cytometry and cytometric bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using single-cell RNA-sequencing (RNA-seq) and paired survival analyses. Results: The CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD-1/CTLA-4 blockade and both CD8 þ T-cell infiltration and therapeutic efficacy were CXCR3 dependent. In both murine models and patients undergoing immunotherapy, macrophages were the predominant source of CXCL9 and their depletion abrogated CD8 þ T-cell infiltration and the therapeutic efficacy of dual ICB. Single-cell RNA-seq analysis of patient tumor-infiltrating lymphocytes (TIL) revealed that CXCL9/ 10/11 was predominantly expressed by macrophages following ICB and we identified a distinct macrophage signature that was associated with positive responses to ICB. Conclusions: These data underline the fundamental importance of macrophage-derived CXCR3 ligands for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient responses.

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Section: Discussionsupporting

confidence: 89%

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

House

Savas

Lai

et al. 2020

Clinical Cancer Research

422

320

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“…[72] Furthermore, a novel CXCL10-EGFRvIII fusion protein (IP10-scFv) with CTLs administration succeeded to induce tumor infiltrating lymphocytes and prolong survival, using a glioma mouse model. [73, 74] Since CXCL11 contributes to inducing Treg migration or promoting Tr1 and Th2 cells polarization, CXCL11-dependent therapy may be controversial as a new target for cancer therapy. In a mesothelioma mouse model, a tumor-selective oncolytic vaccinia virus with CXCL11 reportedly enhanced tumor-infiltrating CTLs and NK cells, but not CD4+ T cells, and prolonged survival.…”

Section: Cxcl9 Cxcl10 Cxcl11/cxcr3 Axis a Target For Cancer Treatmentmentioning

confidence: 99%

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

Tokunaga

Zhang

Naseem

et al. 2018

Cancer Treatment Reviews

965

779

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Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.

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“…They can act as a synergistic factor to promote T cell activation and break down the immune tolerance of tumors. 9 They have chemotaxis and activation effects on monocytes, lymphocytes and neutrophils. 15,16 Chemokines are highly homologous and can be classified into C, CC, CXC and CX3C subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…IP10 can act as a synergistic factor to promote T cell activation and break down the immune tolerance of tumors. 9 It can enhance the chemotaxis and activation of monocyte macrophages, T cells and B cells, subsequently promoting the secretion of various cytokines to inhibit tumor growth. [9][10][11][12] It plays an important role in many diseases such as cancer, viral hepatitis, graft rejection and tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

“…9 It can enhance the chemotaxis and activation of monocyte macrophages, T cells and B cells, subsequently promoting the secretion of various cytokines to inhibit tumor growth. [9][10][11][12] It plays an important role in many diseases such as cancer, viral hepatitis, graft rejection and tuberculosis. [10][11][12][13] Therefore, in this study, IP10 and CDR3 were linked with single-chain antibody (scfv) and exotoxin gene muton of Pseudomonas aeruginosa (PE40) to construct novel immune cell elements IP10-CDR3scfv and IP10-CDR3-PE40scfv through genetic engineering technology.…”

Section: Introductionmentioning

confidence: 99%

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<p>IP10-CDR3 Reduces The Viability And Induces The Apoptosis Of Ovarian Cancer Cells By Down-Regulating The Expression Of Bcl-2 And Caspase 3</p>

Chen

Zhuang

et al. 2019

OTT

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This study aimed to explore the effects of interferon-γ inducible protein 10 (IP10) and complementarity-determining region 3 (CDR3) of T cells receptor on ovarian cancer cells and the involved mechanisms. Methods: IP10 and CDR3 were linked with single-chain antibody (scfv) and exotoxin gene muton of Pseudomonas aeruginosa (PE40) to construct IP10-CDR3scfv and IP10-CDR3-PE40scfv. Then, we constructed pcDNA3.1-IP10-CDR3scfv and pcDNA3.1-IP10-CDR3-PE40scfv plasmids which were proved by HindIII/EcoRI digestion. SKOV3 cells and HOSEpiC cells were incubated with fluorescein isothiocyanate (FITC) labeled IP10-CDR3scfv and IP10-CDR3-PE40scfv proteins and protein levels were examined by flow cytometry. After gene transfection, SKOV3 cells were divided into four groups: Control, pcDNA3.1(+) negative control (NC) (pcDNA3.1(+) NC transfection), IP10-CDR3scfv (IP10-CDR3scfv transfection) and IP10-CDR3-PE40scfv (IP10-CDR3-PE40scfv transfection). Levels of IP10, CDR3, Caspase-3, cleaved Caspase-3 and Bcl-2 were determined by RT-PCR and Western blot. Cell viability and apoptosis were investigated by CCK-8 assay and Annexin V-FITC/PI assay, respectively. Results: The levels of FITC-labeled IP10-CDR3scfv and IP10-CDR3-PE40scfv proteins in the SKOV3+IP10-CDR3scfv group and the SKOV3+IP10-CDR3-PE40scfv group were remarkably higher than that in the SKOV3 group (P<0.05). So was the HOSEpiC related groups. There was no obvious difference in the levels of IP10, CDR3, Caspase-3, cleaved Caspase-3 and Bcl-2 between the control group and the pcDNA3.1(+) NC group. However, compared with the control group, the levels of Caspase-3 and Bcl-2 were reduced notably and the levels of IP10, CDR3 and cleaved Caspase-3 were elevated sharply in the IP10-CDR3scfv and IP10-CDR3-PE40scfv groups (P<0.05). The control group and the pcDNA3.1 (+) NC group demonstrated similar cell viability and apoptosis. However, compared with the control group, cell viability in the IP10-CDR3scfv and IP10-CDR3-PE40scfv groups decreased significantly and cell apoptosis increased (P<0.05). Conclusion: IP10-CDR3 could reduce the viability and induce the apoptosis of ovarian cancer cells by down-regulating the expression of Bcl-2 and Caspase-3.

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Human IP10-scFv and DC-induced CTL synergistically inhibit the growth of glioma in a xenograft model

Cited by 19 publications

References 49 publications

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

<p>IP10-CDR3 Reduces The Viability And Induces The Apoptosis Of Ovarian Cancer Cells By Down-Regulating The Expression Of Bcl-2 And Caspase 3</p>

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