IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors

Kerkar, Sid P.; Goldszmid, Romina S.; Muranski, Pawel; Chinnasamy, Dhanalakshmi; Yu, Zhiya; Reger, Robert; Leonardi, Anthony; Morgan, Richard A.; Wang, Ena; Marincola, Francesco M.; Trinchieri, Giorgio; Rosenberg, Steven A.; Restifo, Nicholas P.

doi:10.1172/jci58814

Cited by 286 publications

(255 citation statements)

References 56 publications

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“…Kerkar and colleagues found that IL-12 could reprogram immunosuppressive DCs to regain immunostimulating functions that promote anti-tumor T cells. 35 It is known that maturation of DCs is associated with increased expression of MHC class II and co-stimulatory molecules, such as CD40, CD80 and CD86 on the cell surface, 36 and that interaction of CD40 and CD40L is essential for the differentiation of DCs from immature into fully mature phenotype that are able to prime adaptive T cell responses. 37 In agreement with these reports, our results showed that RT/IL-12 treatment greatly increased the levels of MHC class II and co-stimulatory molecules CD40 and CD86 on DCs (Figure 5), suggesting that these DCs may gain antigen-presentation functions to promote antitumor T cell responses.…”

Section: Discussionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8+ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

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Section: Discussionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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“…99,100 Alternative ways of cell-mediated delivery of IL-12 have taken advantage of the tumor-homing capacity of mesenchymal stem cells 101 or transfer of tumor-infiltrating lymphocytes. The latter approach has been used to deliver CD8 þ T cells specific for melanoma antigens [102][103][104] or engineered to express a chimeric antigen receptor (CAR) against CD19 in B-cell lymphomas. 105 The administered IL-12 was found to activate myeloid cells by increasing the expression of Fas and cross-presentation, leading to the stimulation of tumor antigen-specific CD8 T cells and regression of established tumors 102,106 (Figure 1).…”

Section: Therapeutic Effects Of Il-12 In Preclinical Modelsmentioning

confidence: 99%

“…The latter approach has been used to deliver CD8 þ T cells specific for melanoma antigens [102][103][104] or engineered to express a chimeric antigen receptor (CAR) against CD19 in B-cell lymphomas. 105 The administered IL-12 was found to activate myeloid cells by increasing the expression of Fas and cross-presentation, leading to the stimulation of tumor antigen-specific CD8 T cells and regression of established tumors 102,106 (Figure 1). More recently, the development of novel approaches that direct IL-12 activity to the tumor site focus on immunocytokines, for example, the fusion of the cytokine to an antibody that binds specifically to the tumor vasculature, 107,108 or to exposed deoxyribonucleic acid (DNA) in the necrotic core of a tumor.…”

Section: Therapeutic Effects Of Il-12 In Preclinical Modelsmentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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“…They found that anti-tumor activity depended on the ability of the myeloid-derived cells, but not lymphocytes or NK cells, to respond to IL-12. In addition, this T cell-delivered IL-12 resulted in significant reprogramming of multiple myeloidderived cell populations, including MDSCs, macrophages, and DCs within the tumor [102]. Chmielewski and colleagues took a different approach by engineering cytotoxic T cells with a chimeric antigen receptor (CAR) with specificity for a tumor-associated antigen.…”

Section: Therapeutic Reprogramming Of Tumor-associated Macrophagesmentioning

confidence: 99%

Monocytes and Macrophages in Cancer: Development and Functions

Richards

Hettinger

Feuerer

2012

Cancer Microenvironment

166

122

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Monocytes and tumor-associated macrophages are part of the myeloid family, a group of hematopoietic derived cells. Monocytes are direct precursors of hematopoietic stem cell-derived macrophages. After their recruitment into the tumor tissue, they can differentiate into tumor-associated macrophages, a very heterogeneous cell population in terms of phenotype and pro-tumor function, supporting tumor initiation, local progression and distant metastasis. Therefore, targeting monocytes and macrophages is a promising immunotherapeutic approach. This review will focus on the development of monocytes as macrophage precursors, the functions of tumorassociated macrophages and the possibility of interfering with tumor development and progression by targeting these myeloid cells.

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IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors

Cited by 286 publications

References 56 publications

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

New insights into IL-12-mediated tumor suppression

Monocytes and Macrophages in Cancer: Development and Functions

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