Recombined CC chemokine ligand 2 into B16 cells induces production of Th2-dominanted cytokines and inhibits melanoma metastasis

Hu, Kaimeng; Xiong, Jie; Ji, Kaihong; Sun, Hongyu; Wang, Jing; Liu, Houqi

doi:10.1016/j.imlet.2007.07.004

Cited by 15 publications

(13 citation statements)

References 34 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, CCL2 reportedly induces the recruitment of macrophages and CTL and induces angiogenesis and matrix remodeling (35)(36)(37). Depending upon the level of expression of CCL2, this chemokine can either promote or reduce melanoma tumor growth (38)(39)(40)(41)(42). This type of dichotomy in the role of chemokines on the immune system may be tightly linked to the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Knight¹,

Ngiow²,

Li³

et al. 2013

J. Clin. Invest.

254

188

View full text Add to dashboard Cite

The BRAF mutant, BRAF V600E , is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF V600E metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF V600E -induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of Braf V600E -driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both Braf V600E mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8 + T/FoxP3 + CD4 + T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Knight¹,

Ngiow²,

Li³

et al. 2013

J. Clin. Invest.

254

188

View full text Add to dashboard Cite

show abstract

“…Fourth, CCL2 was observed to serve as a chemoattractant for T-regs (5). Finally, CCL2 is also recognized to exert direct immuno-inhibitory (protumorigenic) effects on T-cell function (6,7), such as inhibiting T-cell effector functions and switching T-cell differentiation toward Th2-like cells (8).…”

Section: Discussionmentioning

confidence: 99%

“…CCL2 was shown to play a role in tumorigenesis and metastases in several solid tumors, including breast cancer, melanoma, and prostate cancer (8,9). The role of CCL2 in non-small-cell lung cancer (NSCLC) remains controversial, with evidence of both protumorigenic and antitumorigenic effects.…”

mentioning

confidence: 99%

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

Fridlender

Kapoor²,

Buchlis³

et al. 2011

Am J Respir Cell Mol Biol

130

View full text Add to dashboard Cite

The role of chemokines in the pathogenesis of lung cancer has been increasingly appreciated. Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) is secreted from tumor cells and associated tumor stromal cells. The blockade of CCL2, as mediated by neutralizing antibodies, was shown to reduce tumorigenesis in several solid tumors, but the role of CCL2 in lung cancer remains controversial, with evidence of both protumorigenic and antitumorigenic effects. We evaluated the effects and mechanisms of CCL2 blockade in several animal models of non-small-cell lung cancer (NSCLC). Anti-murine-CCL2 monoclonal antibodies were administered in syngeneic flank and orthotopic models of NSCLC. CCL2 blockade significantly slowed the growth of primary tumors in all models studied, and inhibited lung metastases in a model of spontaneous lung metastases of NSCLC. In contrast to expectations, no significant effect of treatment was evident in the number of tumor-associated macrophages recruited into the tumor after CCL2 blockade. However, a change occurred in the polarization of tumorassociated macrophages to a more antitumor phenotype after CCL2 blockade. This was associated with the activation of cytotoxic CD8 1 T lymphocytes (CTLs). The antitumor effects of CCL2 blockade were completely lost in CB-17 severe combined immunodeficient mice or after CD8 T-cell depletion. Our data from NSCLC models show that CCL2 blockade can inhibit the tumor growth of primary and metastatic disease. The mechanisms of CCL2 blockade include an alteration of the tumor macrophage phenotype and the activation of CTLs. Our work supports further evaluation of CCL2 blockade in thoracic malignancies.Keywords: tumor immunology; CCL2; lung cancer; mesothelioma; tumor-associated macrophages Tumor-induced immunosuppression is one of the most important ways by which cancer cells alter their microenvironments and inhibit endogenous antitumor immune responses (1, 2). One important, immunologically active factor secreted from tumor cells and associated tumor stromal cells is monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a member of the CC (b) chemokine superfamily. Although first identified as a chemokine produced by tumors and macrophages that could induce the migration of monocytes (3), CCL2 has a number of immunosuppressive properties, such as the attraction of T-regulatory cells and endothelial cells to sites of inflammation (3-5), and the direct inhibition of CD8 1 T-cell effector functions (6, 7).CCL2 was shown to play a role in tumorigenesis and metastases in several solid tumors, including breast cancer, melanoma, and prostate cancer (8, 9). The role of CCL2 in non-small-cell lung cancer (NSCLC) remains controversial, with evidence of both protumorigenic and antitumorigenic effects. Human NSCLC tumors secrete CCL2 at higher levels than normal lung tissue, and in some studies, high concentrations were associated with metastatic disease (10, 11). In contrast, the transfection of NSCLC lines with CCL2 does not alter the metastatic pote...

show abstract

“…Of note, patients with pancreatic cancer and high circulating levels of CCL2 have significantly higher survival rate than those with low CCL2 serum levels. Thus, the biological significance of CCL2 in cancer progression appears particularly complex and may vary according to the tumor types and progression since this chemokine may impair cancer cell cycle progression and survival, via the inducible NO synthase and NO-mediated G1-arrest (Monti et al, 2003;Hu et al, 2007;Loberg et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells

et al. 2008

View full text Add to dashboard Cite

From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasisrelated genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6-and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.

show abstract

Recombined CC chemokine ligand 2 into B16 cells induces production of Th2-dominanted cytokines and inhibits melanoma metastasis

Cited by 15 publications

References 34 publications

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells

Contact Info

Product

Resources

About

Recombined CC chemokine ligand 2 into B16 cells induces production of Th2-dominanted cytokines and inhibits melanoma metastasis

Cited by 15 publications

References 34 publications

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8+ Cells

Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells

Contact Info

Product

Resources

About

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells