Kerkar, SP, Goldszmid, RS, Muranski, P, Chinnasamy, D, Yu, Z, Reger, RN et al.. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J Clin Invest 121: 4746-4757

Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1502, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 11/2011; 121(12):4746-57. DOI: 10.1172/JCI58814
Source: PubMed


Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8(+) T cells to secrete the inflammatory cytokine IL-12 improved their therapeutic efficacy in the B16 mouse model of established melanoma. Here, we report the mechanism underlying this finding. Surprisingly, direct binding of IL-12 to receptors on lymphocytes or NK cells was not required. Instead, IL-12 sensitized bone marrow-derived tumor stromal cells, including CD11b(+)F4/80(hi) macrophages, CD11b(+)MHCII(hi)CD11c(hi) dendritic cells, and CD11b(+)Gr-1(hi) myeloid-derived suppressor cells, causing them to enhance the effects of adoptively transferred CD8(+) T cells. This reprogramming of myeloid-derived cells occurred partly through IFN-γ. Surprisingly, direct presentation of antigen to the transferred CD8(+) T cells by tumor was not necessary; however, MHCI expression on host cells was essential for IL-12-mediated antitumor enhancements. These results are consistent with a model in which IL-12 enhances the ability of CD8(+) T cells to collapse large vascularized tumors by triggering programmatic changes in otherwise suppressive antigen-presenting cells within tumors and support the use of IL-12 as part of immunotherapy for the treatment of solid tumors.

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    • "Additional data from this model suggest that anti-tumor T cell responses are initiated in solid tumors, but immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO [24]. Adoptive transfer of melanoma-specific CD8 T cells engineered to express IL-12 was found to cause tumor involution via collapse of tumor stroma and vasculature [25]. IL-12 is known to promote IFNγ secretion, which in turn can induce IDO expression in myeloid cell subsets [reviewed in [5]]. "
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    ABSTRACT: Background Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction. Methods To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy. Results Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival. Conclusions Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.
    Full-text · Article · Jul 2014
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    • "The anti-tumor effects of IL-12 are well documented (21). IL-12 enhances the ability of CD8+ T cells to cause the regression of large established tumors by potently stimulating the production of high-levels of IFN-γ, resulting in an increase in the cross-presentation of tumor-antigens and the reversal of suppressive functions of myeloid-derived suppressor cells, alternatively activated macrophages, and dendritic cells (22). These changes subsequently lead to the collapse of the tumor stroma and the regression of large established masses (22, 23). "
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    ABSTRACT: T lymphocytes first carried foreign genes safely into humans over two decades ago. Since these pioneering studies, scientific techniques to better understand the genomic landscape of cells has directly led to a more sophisticated appreciation of the diversity, functional complexity, and therapeutic potential of T cells. Through the use of mouse models, we now know the function of the many genes that are critical for T cells to recognize foreign, mutated, or self-antigens and the factors responsible for the lineage diversification of T cells that lead to inhibitory or stimulatory immune responses. This knowledge combined with well-established modalities to introduce genes into T cells allows for the design of effector and memory CD8 and CD4 T lymphocytes specific for viral, fungal, bacterial, parasitic, and tumor-antigens and to design regulatory lymphocytes specific for the self-antigens responsible for autoimmune and inflammatory diseases. Here, I review strategies for designing the ideal T cell by introducing genes controlling (1) the secretion of cytokines/chemokines and their receptors, (2) T-cell receptor specificity, (3) chimeric-antigen receptors that enable for the recognition of surface antigens in an MHC-independent fashion, (4) co-stimulatory/inhibitory surface molecules, and (5) disease defining single-gene factors.
    Full-text · Article · Sep 2013 · Frontiers in Immunology
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    • "IL-12 has been proven to be effective in controlling tumor growth and metastases. The mechanisms responsible for the anti-tumor effects of IL-12 include: promoting IFN-γ production, anti-angiogenesis , triggering programmatic changes in suppressive cellular components within tumors, and enhancing lytic abilities of CTLs, NK cells and NKT cells to eradicate tumors [52] [53]. However, IL-12 treatment of human cancer patients is associated with severe side effects, which may be due to its excessive pro-inflammatory effects. "
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    ABSTRACT: Cytotoxic T lymphocyte (CTL) response is a critical component of the immune response to tumors, therefore optimal induction of CTL responses to tumor antigens is highly desired for developing efficient cancer immunotherapy. IL-27 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3), and a p35-related subunit, p28. IL-27 functions through IL-27R and has been shown to have potent anti-tumor activity via activation of a variety of immune components, including anti-tumor CD8(+) T cell responses. However, the exact mechanisms of how IL-27 enhances anti-tumor CD8(+) T cell responses are not fully understood. In this paper we mainly discuss the evidences that suggest novel mechanisms by which IL-27 enhances anti-tumor CTL responses, including IL-27 inhibition of activation-induced cell death; the phenotypes of IL-27-stimulated CTLs; IL-27-induced CTL IL-10/IL-21 production and IL-27-mediated suppression of regulatory T cell responses. These evidences suggest that IL-27 may have a great potential to be utilized in boosting anti-tumor CTL responses in human cancer patients.
    Full-text · Article · Aug 2013 · American Journal of Translational Research
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