Immune targeting in breast cancer Cimino-Mathews, Ashley; Foote, Jeremy B; Emens, Leisha A
Oncology (Williston Park, N.Y.),
05/2015, Volume:
29, Issue:
5
Journal Article
Peer reviewed
The immune system is active in breast cancer, playing a dual role in tumor progression and in immune surveillance. Infiltrating immune cells are both prognostic and predictive of response to standard ...breast cancer therapies. Breast cancer vaccines can activate and expand tumor-specific T cells, but have enjoyed minimal clinical success to date. Immune checkpoint blockade is a new approach to cancer immunotherapy, with documented clinical responses in diverse tumor types. Interest in breast cancer immunotherapy has been reignited by recent reports of objective responses in metastatic triple-negative breast cancer with both pembrolizumab (a programmed cell death protein 1 PD-1 antagonist) and MPDL3280A (a programmed cell death ligand 1 PD-L1 antagonist). Rational strategies for combination immunotherapy that expand and promote the trafficking of tumor-specific T cells, support their activity at the tumor site, and abrogate pathways of immune suppression within breast tumors are most likely to result in objective responses that translate into long-term disease control and cure.
Obesity is a prominent health issue worldwide and directly impacts pancreatic health, with obese individuals exhibiting a significant risk for increasing pancreatic ductal adenocarcinoma (PDAC). ...Several factors potentially explain the increased risk for the development of PDAC, including obesity-induced chronic inflammation within and outside of the pancreas, development of insulin resistance and metabolic dysfunction, promotion of immune suppression within the pancreas during inflammation, pre- and malignant stages, variations in hormones levels (adiponectin, ghrelin, and leptin) produced from the adipose tissue, and acquisition of somatic mutations in tumor once- and suppressor proteins critical for pancreatic tumorigenesis. In this manuscript, we will explore the broad impact of these obesity-induced risk factors on the development and progression of PDAC, focusing on changes within the tumor microenvironment (TME) as they pertain to prevention, current therapeutic strategies, and future directions for targeting obesity management as they relate to the prevention of pancreatic tumorigenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pancreatic cancer (PC) remains a leading cause of mortality worldwide due to the absence of early detection methods and the low success rates of traditional therapeutic strategies. Drug resistance in ...PC is driven by its desmoplastic stroma, which creates a barrier that shields cancer niches and prevents the penetration of drugs. The PC stroma comprises heterogeneous cellular populations and non-cellular components involved in aberrant ECM deposition, immunosuppression, and drug resistance. These components can influence PC development through intricate and complex crosstalk with the PC cells. Understanding how stromal components and cells interact with and influence the invasiveness and refractoriness of PC cells is thus a prerequisite for developing successful stroma-modulating strategies capable of remodeling the PC stroma to alleviate drug resistance and enhance therapeutic outcomes. In this review, we explore how non-cellular and cellular stromal components, including cancer-associated fibroblasts and tumor-associated macrophages, contribute to the immunosuppressive and tumor-promoting effects of the stroma. We also examine the signaling pathways underlying their activation, tumorigenic effects, and interactions with PC cells. Finally, we discuss recent pre-clinical and clinical work aimed at developing and testing novel stroma-modulating agents to alleviate drug resistance and improve therapeutic outcomes in PC.
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•Pancreatic cancer (PC) is surrounded by a thick desmoplastic stroma that promotes drug resistance.•Aberrant extracellular matrix deposition prevents drug penetration and enhances PC survival.•Cancer-associated fibroblasts are heterogeneous and can enhance PC progression through various signaling mechanisms.•Tumor-associated macrophages promote immunosuppression in the PC stroma.•Clinical trials are underway to investigate the effects of stroma-modulating drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondrial dysfunction is one of the hallmarks of aging. Changes in sebaceous gland (SG) function and sebum production have been reported during aging. This study shows the direct effects of ...mitochondrial dysfunction on SG morphology and function. A mitochondrial DNA (mtDNA) depleter mouse was used as a model for introducing mitochondrial dysfunction in the whole animal. The effects on skin SGs and modified SGs of the eyelid, lip, clitoral, and preputial glands were characterized. The mtDNA depleter mice showed gross morphologic and histopathologic changes in SGs associated with increased infiltration by mast cells, neutrophils, and polarized macrophages. Consistently, there was increased expression of proinflammatory cytokines. The inflammatory changes were associated with abnormal sebocyte accumulation of lipid, defective sebum delivery at the skin surface, and the up-regulation of key lipogenesis-regulating genes and androgen receptor. The mtDNA depleter mice expressed aging-associated senescent marker. Increased sebocyte proliferation and aberrant expression of stem cell markers were observed. These studies provide, for the first time, a causal link between mitochondrial dysfunction and abnormal sebocyte function within sebaceous and modified SGs throughout the whole body of the animal. They suggest that mtDNA depleter mouse may serve as a novel tool to develop targeted therapeutics to address SG disorders in aging humans.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
NAD, a key co-enzyme required for cell metabolism, is synthesized via two pathways in most organisms. Since schistosomes apparently lack enzymes required for de novo NAD biosynthesis, we evaluated ...whether these parasites, which infect >200 million people worldwide, maintain NAD homeostasis via the NAD salvage biosynthetic pathway. We found that intracellular NAD levels decline in schistosomes treated with drugs that block production of nicotinamide or nicotinamide mononucleotide-known NAD precursors in the non-deamidating salvage pathway. Moreover, in vitro inhibition of the NAD salvage pathway in schistosomes impaired egg production, disrupted the outer membranes of both immature and mature parasites and caused loss of mobility and death. Inhibiting the NAD salvage pathway in schistosome-infected mice significantly decreased NAD levels in adult parasites, which correlated with reduced egg production, fewer liver granulomas and parasite death. Thus, schistosomes, unlike their mammalian hosts, appear limited to one metabolic pathway to maintain NAD-dependent metabolic processes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically-engineered pig kidney or heart transplantation. As regimens based on a calcineurin ...inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin (ATG), an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 weeks, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically-approved agent, eg, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway is yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
Many bacteria-associated polysaccharides induce long-lived Ab responses that protect against pathogenic microorganisms. The maintenance of polysaccharide-specific Ab titers may be due to long-lived ...plasma cells or ongoing Ag-driven B cell activation due to polysaccharide persistence. BALB/c and V(H)J558.3 transgenic mice respond to α1→3-dextran (DEX) by generating a peak anti-DEX response at 7 d, followed by maintenance of serum Ab levels for up to 150 d. Analysis of the cellular response to DEX identified a population of short-lived, cyclophosphamide-sensitive DEX-specific plasmablasts in the spleen, and a quiescent, cyclophosphamide-resistant DEX-specific Ab-secreting population in the bone marrow. BrdU pulse-chase experiments demonstrated the longevity of the DEX-specific Ab-secreting population in the bone marrow. Splenic DEX-specific plasmablasts were located in the red pulp with persisting DEX-associated CD11c(+) dendritic cells 90 d after immunization, whereas DEX was not detected in the bone marrow after 28 d. Selective depletion of short-lived DEX-specific plasmablasts and memory B1b B cells using cyclophosphamide and anti-CD20 treatment had a minimal impact on the maintenance of serum anti-DEX Abs. Collectively, these findings demonstrate that the maintenance of serum polysaccharide-specific Abs is the result of continuous Ag-driven formation of short-lived plasmablasts in the spleen and a quiescent population of Ab-secreting cells maintained in the bone marrow for a long duration.
Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We ...examined to what extent preexisting antigen-specific tolerance influenced the efficacy of
delivery of a potent STING-activating cyclic dinucleotide (CDN), ADU S-100, against established HER-2
breast tumors. ADU S-100 induced HER-2-specific CD8
T-cell priming and durable tumor clearance in 100% of nontolerant parental FVB/N mice. In contrast, ADU S-100 did not sufficiently prime HER-2-specific CD8
T cells in tolerant neu/N mice, resulting in only delayed tumor growth and tumor clearance in 10% of the mice. No differences in IFNβ production, DC priming, or HER-2-specific CD8
T-cell trafficking were detected between FVB/N and neu/N mice. However, activation and expansion of HER-2-specific CD8
T cells were defective in neu/N mice. Immune cell infiltrates of untreated tumor-bearing neu/N mice expressed high numbers of PD1 and OX40 receptors on their CD8
T cells, and PD-L1 was highly expressed on both myeloid and tumor cells. Modulating PD-L1 and OX40 receptor signaling combined with intratumoral ADU S-100 administration enhanced HER-2-specific CD8
T-cell activity, clearing tumors in 40% of neu/N mice. Thus, intratumoral STING agonists could potently prime tumor antigen-specific CD8
T-cell responses, and adding PD-L1 blockade and OX40 receptor activation can overcome antigen-enforced immune tolerance to induce tumor regression.
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Lewisite is a strong vesicating and chemical warfare agent. Because of the rapid transdermal absorption, cutaneous exposure to lewisite can also elicit severe systemic injury. Lewisite (2.5, 5.0, and ...7.5 mg/kg) was applied to the skin of Ptch1+/−/SKH‐1 mice and acute lung injury (ALI) was assessed after 24 hours. Arterial blood gas measurements showed hypercapnia and hypoxemia in the lewisite‐exposed group. Histological evaluation of lung tissue revealed increased levels of proinflammatory neutrophils and a dose‐dependent increase in structural changes indicative of injury. Increased inflammation was also confirmed by altered expression of cytokines, including increased IL‐33, and a dose‐dependent elevation of CXCL1, CXCL5, and GCSF was observed in the lung tissue. In the bronchoalveolar lavage fluid of lewisite‐exposed animals, there was a significant increase in HMGB1, a damage‐associated molecular pattern molecule, as well as elevated CXCL1 and CXCL5, which coincided with an influx of neutrophils to the lungs. Complete blood cell analysis revealed eosinophilia and altered neutrophil–lymphocyte ratios as a consequence of lewisite exposure. Mean platelet volume and RBC distribution width, which are predictors of lung injury, were also increased in the lewisite group. These data demonstrate that cutaneous lewisite exposure causes ALI and may contribute to mortality in exposed populations.
Lewisite is a strong vesicating and chemical warfare agent. Because of rapid transdermal absorption, cutaneous exposure to lewisite can also elicit severe systemic injury, including to the lungs. However, the effects of cutaneous lewisite exposure on the lungs have not been systematically evaluated. In this study, the authors sought to characterize acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) in mice exposed to cutaneous lewisite.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
To determine the extent to which the gut microbiome influences systemic autoimmunity in a mouse model of lupus.
Methods
We generated germ‐free (GF) lupus‐prone BXD2 mice, which under normal ...conditions develop spontaneous germinal centers (GCs) and high titers of serum autoantibodies. GF status was confirmed by gut bacterial culture. The autoimmune phenotypes of 6‐ and 12‐month‐old gnotobiotic GF BXD2 mice and specific pathogen–free (SPF) BXD2 mice were compared. Serum levels of autoantibodies were measured by enzyme‐linked immunosorbent assay. Histologic sections of the mouse kidney and joints were evaluated. Flow cytometry was used to analyze GCs and age‐associated B cells. CD4+ T cells were analyzed for PD‐1+ICOS+ activated T cells, T follicular regulatory (Tfr) cells (Foxp3+CD25+ PD‐1+CXCR5+), and PD‐1+ICOS+ T cells expressing interleukin‐17A (IL‐17A) or interferon‐γ (IFNγ) after stimulation with phorbol myristate acetate (PMA)/ionomycin.
Results
In 6‐month‐old mice, GF status did not affect splenomegaly, GC B cells, age‐associated B cells, or serum autoantibody levels, except for IgG antihistone. GF BXD2 mice exhibited a significantly higher percentage of Tfr cells compared to their SPF counterparts (P < 0.05). At 12 months of age, however, GF BXD2 mice had significantly diminished IgG autoantibody levels and a lower percentage of GC B cells and age‐associated B cells (P < 0.05). Following stimulation with PMA/ionomycin, PD‐1+ICOS+ CD4+ T cells expressed significantly lower IL‐17A, but not IFNγ, levels in GF BXD2 mice compared to SPF BXD2 mice (P < 0.01). SPF BXD2 mice and GF BXD2 mice developed equivalent renal and joint disease with no significant differences in severity.
Conclusion
Our results suggest a model in which genetics plays a dominant role in determining the initial development of autoimmunity. In contrast, gut microbiomes may regulate the persistence of certain aspects of systemic autoimmunity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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