A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice

Liechtenstein, Therese; Pérez-Janices, Noemí; Gato, María; Caliendo, Fabio; Kochan, Grazyna; Blanco‐Luquin, Idoia; Arce, Frederick; Guerrero-Setas, David; Fernández‐Irigoyen, Joaquín; Santamaría, Enrique; Breckpot, Karine; Escors, David

doi:10.18632/oncotarget.2279

Cited by 64 publications

(78 citation statements)

References 40 publications

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“…Unlike CD80, CD86 is a co-stimulatory molecule usually associated with immunogenic antigen-presenting cells (APCs) (20), but not with immunosuppressive functioning of MDSCs (21, 22). The tumor-infiltrating Ly6G + / MHCII + cells from WT host expressed low levels of surface CD86.…”

Section: Resultsmentioning

confidence: 99%

Targeting Autocrine CCL5–CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity

Mai

et al. 2017

Cancer Research

129

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The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of ccl5-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the ccl5-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8+ T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between “immune CCR5” levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust anti-tumor immunities. Our study suggests that the myeloid CCL5-CCR5 axis is an excellent target for cancer immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Targeting Autocrine CCL5–CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity

Mai

et al. 2017

Cancer Research

129

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“…Nevertheless, the induction of ICD may be one of the mechanisms that underlie the success of adjuvant and neo-adjuvant BC chemotherapy. Moreover, the fact that additional agents used in combinatorial regimens, such as 5-fluorouracil, cyclophosphamide, and taxanes, can boost the immunogenicity of malignant cells 61,86 , or selectively deplete MDSCs and T reg cells [87][88][89] , suggests that the outcome of BC therapy may be-at least partially-linked to the stimulation (or de-inhibition) of tumor-targeting immune responses.…”

Section: Type I Interferonsmentioning

confidence: 99%

Natural and therapy-induced immunosurveillance in breast cancer

Kroemer

Senovilla

Galluzzi

et al. 2015

Nat Med

270

199

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The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell-dependent tumor-specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.

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“…MDSCs are one such class of cells that can secrete inhibitory cytokines 21, 22 and can differentiate into different heterogeneous populations of myeloid cells that inhibit immune function 23. Previous studies have shown that MDSCs can inhibit the differentiation of effector Th1 cells resulting in immune incompetence and contributing to the development and progression of tumors 24, 25.…”

Section: Discussionmentioning

confidence: 99%

Mouse IP-10 Gene Delivered by Folate-modified Chitosan Nanoparticles and Dendritic/tumor Cells Fusion Vaccine Effectively Inhibit the Growth of Hepatocellular Carcinoma in Mice

Hu¹,

Chen²,

Zhou³

et al. 2017

Theranostics

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Dendritic cells (DC) and tumor cell fusion vaccine (DC/tumor cell fusion vaccine) is considered an effective approach in cancer biotherapy. However, its therapeutic effects in early clinical trials have been suboptimal partially due to the immunosuppressive tumor environment. In this study, we used nanoparticles of folate (FA)-modified chitosan, a non-viral vector capable of targeting tumor cells with high expression of FA receptors. FA-chitosan nanoparticles were used as biological carriers for the expression plasmid of the mouse interferon-induced protein-10 (mIP-10) gene, a potent chemoattractant for cytotoxic T cells. The combination of FA-chitosan/mIP-10 and DC/tumor cell fusion vaccine against hepatocellular carcinoma (HCC) effectively inhibited the growth of implanted HCC tumors and prolonged the survival of mice. The combination therapy significantly reduced myeloid-derived suppressor cells (MDSC) in mouse spleen, local tumor, and bone marrow while increasing tumor-specific IFN-γ responses. Furthermore, the combination therapy significantly inhibited tumor cell proliferation while promoting their apoptosis. Taken together, our data illustrate that the mIP-10 enhances the anti-tumor effect of DC/tumor cell fusion vaccine by alleviating the immunosuppressive tumor environment.

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A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice

Cited by 64 publications

References 40 publications

Targeting Autocrine CCL5–CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity

Targeting Autocrine CCL5–CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity

Natural and therapy-induced immunosurveillance in breast cancer

Mouse IP-10 Gene Delivered by Folate-modified Chitosan Nanoparticles and Dendritic/tumor Cells Fusion Vaccine Effectively Inhibit the Growth of Hepatocellular Carcinoma in Mice

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