CCL2 is critical for immunosuppression to promote cancer metastasis

Kudo-Saito, Chie; Shirako, Hiromi; Ohike, Misa; Tsukamoto, Nobuo; Kawakami, Yutaka

doi:10.1007/s10585-012-9545-6

Cited by 126 publications

(97 citation statements)

References 40 publications

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“…CCL2 is one of the molecules involved in bone metastatic mechanism (5,6). Surely, CCL2 significantly increased in Snail þ tumor cells, and siRNA-ccl2 injection significantly suppressed Snail þ tumor growth and dissemination/metastasis as shown before (12). However, the siRNA-ccl2 injection hardly suppressed CD45…”

Section: Discussionmentioning

confidence: 94%

Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction

et al. 2013

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Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatinlike glycoprotein secreted by Snail þ tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis-in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45 À ALCAM þ cells derived from bone marrow. CD45 À ALCAM þ cells induced bone metastasis de novo, but they also generated CD8 low T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interferencemediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM þ cells and CD8 low T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM þ cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer. Cancer Res; 73(20); 6185-93. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 94%

Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction

et al. 2013

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“…However, their properties were mainly elucidated not from the tumor-mesenchymal interaction but their genetic back- , LGR5 + 32) , and CD44v6 + 33) . via production of CCL2 and subsequent induction of immunoregulatory dendritic cells (regDC) 38) . .…”

Section: E Tran Et Al Demonstrated the Neo-antigen Krasmentioning

confidence: 99%

Inter-patient and Intra-tumor Heterogeneity in the Sensitivity to Tumor-targeted Immunity in Colorectal Cancer

2017

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“…On the basis of a unique strategy analyzing both tumor cells and host simultaneously, we previously demonstrated that Snail-induced EMT simultaneously causes tumor metastasis and immunosuppression in murine (13) and human system (34). However, the entire mechanism of cancer immunoevasion remains to be fully elucidated.…”

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confidence: 99%

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

et al. 2014

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Human endogenous retroviruses (HERV) are associated with many diseases such as autoimmune diseases and cancer. Although the frequent expression of a variety of HERVs in tumor cells has been demonstrated, their functional contributions in cancer are as yet unclear. Intriguingly, HERVs and other retroviruses include an immunosuppressive domain in their transmembrane envelope proteins, but its mechanism of action and cancer relevance are obscure. In this study, we demonstrate that the human endogenous retrovirus HERV-H has a critical role in tumor metastasis and immune escape. We found that expression of herv-h mRNA was elevated in metastatic tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and in primary tumor tissues from advanced colon cancer. The immunosuppressive peptide H17 derived from HERV-H was sufficient to induce EMT in tumor cells that expressed low levels of HERV-H, and it amplified this event within the tumor microenvironment. H17 also stimulated CCL19 expression in tumor cells, which in turn recruited and expanded a population of pluripotent immunoregulatory CD271 þ cells, which included mesenchymal stem cells and myeloid-derived suppressor cells. In tumor tissues from patients with advanced colon cancer, we confirmed that CD271 þ cells were increased in HERV-H þ CCL19 þ tumor tissues. Notably, RNAi-mediated change of HERV-H or CCL19, or depletion of CD271 þ cells, improved immune responses in vitro and in vivo accompanied by tumor regression. Together, our results argued that HERV-H is a critical determinant of immune escape in cancer, suggesting its candidacy as a promising therapeutic target to treat patients with advanced cancer.

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CCL2 is critical for immunosuppression to promote cancer metastasis

Cited by 126 publications

References 40 publications

Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction

Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction

Inter-patient and Intra-tumor Heterogeneity in the Sensitivity to Tumor-targeted Immunity in Colorectal Cancer

Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

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