The Basis of Oncoimmunology Palucka, A. Karolina; Coussens, Lisa M.
Cell,
03/2016, Letnik:
164, Številka:
6
Journal Article
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Cancer heterogeneity, a hallmark enabling clonal survival and therapy resistance, is shaped by active immune responses. Antigen-specific T cells can control cancer, as revealed clinically by ...immunotherapeutics such as adoptive T-cell transfer and checkpoint blockade. The host immune system is thus a powerful tool that, if better harnessed, could significantly enhance the efficacy of cytotoxic therapy and improve outcomes for cancer sufferers. To realize this vision, however, a number of research frontiers must be tackled. These include developing strategies for neutralizing tumor-promoting inflammation, broadening T-cell repertoires (via vaccination), and elucidating the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity. Such efforts will pave the way for identifying new targets for combination therapies that overcome resistance to current treatments and promote long-term cancer control.
Developing combination therapies with curative potential that harness the power of the immune system to treat cancer will require understanding the diverse mechanisms underlying the cross-talk between immune cells, cancer cells and the tumor microenvironment.
There have been substantial advances in cancer diagnostics and therapies in the past decade. Besides chemotherapeutic agents and radiation therapy, approaches now include targeting cancer ...cell—intrinsic mediators linked to genetic aberrations in cancer cells, in addition to cancer cell—extrinsic pathways, especially those regulating vascular programming of solid tumors. More recently, immunotherapeutics have entered the clinic largely on the basis of the recognition that several immune cell subsets, when chronically activated, foster tumor development. Here, we discuss clinical and experimental studies delineating protumorigenic roles for immune cell subsets that are players in cancer-associated inflammation. Some of these cells can be targeted to reprogram their function, leading to resolution, or at least neutralization, of cancer-promoting chronic inflammation, thereby facilitating cancer rejection.
Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programs behind these changes, we applied systems immunology approaches and profiled ...chromatin accessibility and the transcriptome in PBMCs and purified monocytes, B cells, and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging and identified the silencing of the
gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8
T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study provides a unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associated immunodeficiency.
Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting ...cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103+ dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8+ T cells. CD103+ DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103+ DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103+ DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
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•CD103+ DCs are uniquely able to transport intact antigens to the TdLN and prime CD8+ T cells•CD103+ DCs are required to induce anti-PD-L1-Ab-mediated anti-tumor immunity•Combined FLT3L and poly I:C therapy induces expansion and activation of CD103+ DC progenitors in tumors•Combined FLT3L and poly I:C therapy enhances tumor responses to BRAF and checkpoint blockade
Large numbers of melanoma patients develop resistance to targeted therapy or fail to respond to checkpoint inhibition. Merad and colleagues show that FLT3L and poly I:C combined treatment, which expands and activates CD103+ DC progenitors at the tumor site, enhances tumor responses to BRAF and PD-L1 blockade.
Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models cannot support ...development of human innate immune cells, including myeloid cells and natural killer (NK) cells. Here we describe two mouse strains called MITRG and MISTRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked into their respective mouse loci. The human cytokines support the development and function of monocytes, macrophages and NK cells derived from human fetal liver or adult CD34(+) progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MITRG and MISTRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mouse studies have shown that the immune system can reject tumours, and the identification of tumour antigens that can be recognized by human T cells has facilitated the development of immunotherapy ...protocols. Vaccines against cancer aim to induce tumour-specific effector T cells that can reduce the tumour mass, as well as tumour-specific memory T cells that can control tumour relapse. Owing to their capacity to regulate T-cell immunity, dendritic cells are increasingly used as adjuvants for vaccination, and the immunogenicity of antigens delivered by dendritic cells has now been shown in patients with cancer. A better understanding of how dendritic cells regulate immune responses will allow us to better exploit these cells to induce effective antitumour immunity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Monocytes can give rise to either antigen presenting dendritic cells (DCs) or scavenging macrophages. This differentiation is initiated when monocytes cross the endothelium. But the regulation of DC ...and macrophage differentiation in tissues remains elusive. When stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), monocytes yield DCs. However, we show here that the addition of fibroblasts switches differentiation to macrophages. On contact with monocytes, fibroblasts release IL-6, which up-regulates the expression of functional M-CSF receptors on monocytes. This allows the monocytes to consume their autocrine M-CSF. Thus, the interplay between IL-6 and M-CSF switches monocyte differentiation to macrophages rather than DCs, and IL-6 is an essential factor in the molecular control of antigen presenting cell development.
Recent developments in cancer vaccines Palucka, Karolina; Ueno, Hideki; Banchereau, Jacques
The Journal of immunology (1950),
2011-Feb-01, 2011-02-01, 20110201, Letnik:
186, Številka:
3
Journal Article
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The adoptive transfer of cancer Ag-specific effector T cells in patients can result in tumor rejection, thereby illustrating the immune system potential for cancer therapy. Ideally, one would like to ...directly induce efficient tumor-specific effector and memory T cells through vaccination. Therapeutic vaccines have two objectives: priming Ag-specific T cells and reprogramming memory T cells (i.e., a transformation from one type of immunity to another, for example, regulatory to cytotoxic). Recent successful phase III clinical trials showing benefit to the patients revived cancer vaccines. Dendritic cells (DCs) are essential in generation of immune responses, and as such represent targets and vectors for vaccination. We have learned that different DC subsets elicit different T cells. Similarly, different activation methods result in DCs able to elicit distinct T cells. We contend that a careful manipulation of activated DCs will allow cancer immunotherapists to produce the next generation of highly efficient cancer vaccines.
Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1β in primary breast cancer tumors is linked with advanced disease and originates from ...tumor-infiltrating CD11c
myeloid cells. IL1β production is triggered by cancer cell membrane-derived TGFβ. Neutralizing TGFβ or IL1 receptor prevents breast cancer progression in humanized mouse model. Patients with metastatic HER2
breast cancer display a transcriptional signature of inflammation in the blood leukocytes, which is attenuated after IL1 blockade. When present in primary breast cancer tumors, this signature discriminates patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).
IL1β orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist.
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