A Novel, Low-Cost Alternative to Traditional Glaucoma Surgeries.

Purpose: To investigate the real-world efficacy of a novel, low-cost glaucoma drainage device in canine and human patients. Methods: A retrospective case series of 17 eyes in 14 canines and one eye of a human patient who each underwent novel drainage device implantation is described. This device was constructed by insertion and advancement of a 24-gauge cannula (canine) or 23-gauge cannula (human) perpendicularly through five adjacent tubes of a 25-mm Yeates surgical drain. Results: Of the canine patients, the average follow-up period was 362 days (range, 27-863). The mean preoperative intraocular pressure (IOP) was 50.9 ± 17.9 mm Hg. Following tube surgery, IOP was maintained at <20 mm Hg in 81.3%, 100%, 100%, 85.7%, 100%, and 75.0% of eyes at 1, 2, 3, 6, 9, and 12 months, respectively. Bleb needling and/or revisions were required in five eyes. Enucleations and/or device explantations were performed in five eyes at mean day 140. In the human case, the device was implanted in the right eye of a 64-year-old male with refractory raised IOP (55 mm Hg) despite maximum medical therapy. IOP was well controlled until day 818, when eventual tissue breakdown necessitated device removal. Conclusions: This design represents a novel, low-cost, effective alternative to traditional glaucoma tube devices. Translational Relevance: This device has great potential for use in regions where the needs for glaucoma drainage devices and surgical alternatives to trabeculectomy have not been met. Further development may include tube crimping or fenestration and preoperative loading of slow-release antibiotics and/or anti-metabolite medications within the non-draining lumens.

Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1.

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic ß-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.

TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Diffusion tensor imaging of the visual pathway in dogs with primary angle-closure glaucoma.

OBJECTIVE: To describe measurements of in vivo structures of the visual pathway beyond the retina and optic nerve head associated with canine primary angle-closure glaucoma (PACG). METHODS: A prospective pilot study was conducted using magnetic resonance diffusion tensor imaging (DTI) to obtain quantitative measures of the optic nerve, chiasm, tract, and lateral geniculate nucleus (LGN) in dogs with and without PACG. 3-Tesla DTI was performed on six affected dogs and five breed, age- and sex-matched controls. DTI indices of the optic nerve, optic chiasm, optic tracts, and LGN were compared between normal, unilateral PACG, and bilateral PACG groups. Intra-class correlation coefficient (ICC) was calculated to assess intra-observer reliability. RESULTS: Quantitative measurements of the optic nerve, optic tract, optic chiasm, and LGN were obtained in all dogs. There was a trend for reduced fractional anisotropy (FA) associated with disease for all structures assessed. Compared to the same structure in normal dogs, FA, and radial diffusivity (RD) of the optic nerve was consistently higher in the unaffected eye in dogs with unilateral PACG. Intra-observer reliability was excellent for measurements of the optic nerve (ICC: 0.92), good for measurements of the optic tract (ICC: 0.89) and acceptable for measures of the optic chiasm (ICC: 0.71) and lateral geniculate nuclei (ICC: 0.76). CONCLUSION: Diffusivity and anisotropy measures provide a quantifiable means to evaluate the visual pathway in dogs. DTI has potential to provide in vivo measures of axonal and myelin injury and transsynaptic degeneration in canine PACG.

A technique for shotgun proteomic analysis of the precorneal tear film in dogs with naturally occurring primary glaucoma.

OBJECTIVE: To introduce a protocol for the characterization of protein patterns in tears of dogs with primary angle closure glaucoma (PACG) and primary open-angle glaucoma (POAG). ANIMALS: Nineteen dogs (25 eyes). METHODS: Tear samples were collected using a Schirmer tear strip, from dogs with PACG (PACG-affected eyes, n = 8; unaffected eyes predisposed to PACG, n = 7), POAG (n = 4), and healthy controls (n = 6). Protein precipitation and trypsin digestion were performed for analyses via liquid chromatography-tandem mass spectrometry. Proteins were identified using the SwissProt protein sequence database. Relative protein expression in 17 eyes (15 dogs) was evaluated using Proteome Discoverer 2.0. Pathway analyses were performed to investigate molecular mechanisms associated with primary glaucoma. RESULTS: Unique peptides were identified in 505 proteins, with Major allergen Can f 1 and albumin identified with high confidence. Proteins unique to tears from diseased eyes (PACG: n = 7; POAG: n = 14) were identified. Nucleoside diphosphate was unique to tears in PACG eyes naïve to therapy, while retinal binding protein and NSFL1 cofactor p47 were unique to medicated PACG eyes. Relative expression of 34 proteins differed between disease states. Pathway analyses identified that the 'inflammatory response' was among the top disease/disorders in dogs with primary glaucoma (PACG and POAG) but not in healthy controls. CONCLUSION: Tear samples suitable for mass spectrometry were readily obtained from pet dogs without needing specialized equipment. Further studies to validate the findings and explore potential candidate biomarkers for early disease detection and potential therapeutic targets are indicated.

A rational mouse model to detect on-target, off-tumor CAR T cell toxicity.

Off-tumor targeting of human antigens is difficult to predict in preclinical animal studies and can lead to serious adverse effects in patients. To address this, we developed a mouse model with stable and tunable human Her2 (hHer2) expression on normal hepatic tissue and compared toxicity between affinity-tuned Her2 chimeric antigen receptor T cells (CARTs). In mice with hHer2-high livers, both the high-affinity (HA) and low-affinity (LA) CARTs caused lethal liver damage due to immunotoxicity. In mice with hHer2-low livers, LA-CARTs exhibited less liver damage and lower systemic levels of IFN-γ than HA-CARTs. We then compared affinity-tuned CARTs for their ability to control a hHer2-positive tumor xenograft in our model. Surprisingly, the LA-CARTs outperformed the HA-CARTs with superior antitumor efficacy in vivo. We hypothesized that this was due, in part, to T cell trafficking differences between LA and HA-CARTs and found that the LA-CARTs migrated out of the liver and infiltrated the tumor sooner than the HA-CARTs. These findings highlight the importance of T cell targeting in reducing toxicity of normal tissue and also in preventing off-tumor sequestration of CARTs, which reduces their therapeutic potency. Our model may be useful to evaluate various CARTs that have conditional expression of more than 1 single-chain variable fragment (scFv).

Stereotactic Cortical Atlas of the Domestic Canine Brain.

The domestic canine (canis familiaris) is a growing novel model for human neuroscientific research. Unlike rodents and primates, they demonstrate unique convergent sociocognitive skills with humans, are highly trainable and able to undergo non-invasive experimental procedures without restraint, including fMRI. In addition, the gyrencephalic structure of the canine brain is more similar to that of human than rodent models. The increasing use of dogs for non-invasive neuroscience studies has generating a need for a standard canine cortical atlas that provides common spatial referencing and cortical segmentation for advanced neuroimaging data processing and analysis. In this manuscript we create and make available a detailed MRI-based cortical atlas for the canine brain. This atlas includes a population template generated from 30 neurologically and clinically normal non-brachycephalic dogs, tissue segmentation maps and a cortical atlas generated from Jerzy Kreiner's myeloarchitectonic-based histology atlas. The provided cortical parcellation includes 234 priors from frontal, sensorimotor, parietal, temporal, occipital, cingular and subcortical regions. The atlas was validated using an additional canine cohort with variable cranial conformations. This comprehensive cortical atlas provides a reference standard for canine brain research and will improve and standardize processing and data analysis and interpretation in functional and structural MRI research.

Predictors of Viremia in Postpartum Women on Antiretroviral Therapy.

BACKGROUND: HIV-infected, postpartum women on antiretroviral therapy (ART) have high rates of viremia. We examined predictors of postpartum viremia in the PROMISE study. METHODS: Women with pre-ART CD4 T-cell counts ≥400 cells/mm who started ART during pregnancy were randomized postpartum to continue ART (CTART) or discontinue ART (DCART). Viral load and self-reported adherence were collected every 12 weeks, up to 144 weeks. Women in DCART reinitiated therapy when clinically indicated. Viremia was defined as 2 consecutive viral loads >1000 copies/mL after 24 weeks on ART. Adherence was dichotomized as missing versus not missing ART doses in the past 4 weeks. Predictors of viremia were examined using Cox proportional hazards regression with adherence as a time-varying covariate. RESULTS: Among 802 women in the CTART arm, median age at entry was 27 years and median CD4 T-cell count 696 cells/mm. Of 175 women in CTART with viremia (22%), 141 had resistance data, and 12% had resistance to their current regimen. There was an estimated 0.12 probability of viremia by week 48 and 0.25 by week 144. Predictors of viremia included missed ART doses within the past 4 weeks, younger age, shorter duration of pre-entry ART, and being from the South American/Caribbean region. Of 137 women in DCART who reinitiated therapy, probability of viremia was similar to CTART (0.24 by week 96; 0.27 by week 144). CONCLUSIONS: Rates of postpartum viremia are high and viremia is more likely in younger postpartum women who start ART later in pregnancy. Interventions should target these higher-risk women.

Optical coherence tomography of the retina, nerve fiber layer, and optic nerve head in dogs with glaucoma.

OBJECTIVE: To evaluate the retina and optic nerve head (ONH) in canine eyes predisposed to glaucoma using optical coherence tomography (OCT). ANIMALS: Twenty-five eyes (24 dogs). METHODS: Measures of peripapillary retinal, retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) thickness and ONH parameters were obtained in vivo by OCT of the unaffected eye in dogs diagnosed with unilateral primary glaucoma (predisposed; n = 12) and compared with measures of healthy control eyes (normal; n = 13). Repeatability and intrarater reliability were explored using intraclass correlation coefficients (ICC). RESULTS: Compared to normal eyes, predisposed eyes had a thinner retina in the temporal (P = 0.005), inferior quadrants (P = 0.003), and decreased inner retinal thickness (superior: P = 0.003, temporal: P = 0.001, inferior: P < 0.001, nasal: P = 0.001). Predisposed eyes had a thinner RNFL compared to normal eyes (P = 0.005), and when analyzed in quadrants, it was thinner in the superior (P < 0.001), temporal (P = 0.034), and nasal quadrants (P = 0.001). Repeatability (ICC 0.763-0.835) and intrarater reliability (ICC 0.824-0.942) were good to excellent for measures of retinal thickness and adequate for RNFL measurements (ICC 0.701-0.798). Reliable measurements of optic disk area were obtained and were similar between groups (P = 0.597). Measurements of parameters relying on automated software detection (GCC, optic cup, optic rim) had inadequate repeatability and reliability. CONCLUSION: Statistically significant differences in retinal and RNFL thicknesses were identified in normal and predisposed eyes. Reliable and consistent measurements of variables with manual adjustment of software detected parameters were obtained. Validation of OCT as a diagnostic tool for clinical assessment in canine glaucoma is warranted.

Development of a vision impairment score for the assessment of functional vision in dogs: Initial evidence of validity, reliability, and responsiveness.

AIM: To describe the development and initial validation of a questionnaire measuring functional vision in dogs. METHODS: A 17-item survey was designed to quantify functional vision in dogs. The Vision Impairment Score (VIS) was determined by summing responses to each question. Questions were assigned to one of five subcategories: overall vision, daily activities, peripheral vision, near vision, and distance vision. Content validity was established during development phases, and construct validity via comparing results of known groups (blind vs sighted; normal vs impaired vision; surgery to improve vision vs nonrestorative surgery), and through factor analysis. Concurrent criterion validity was determined with use of a validated health-related quality-of-life (HRQL) assessment tool. Reliability and responsiveness assessments were investigated using intraclass correlation coefficient (ICC) and effect size (ES), respectively. RESULTS: Responses (221) from 201 dog owners were included. Compared to sighted dogs (n = 153), blind dogs (n = 48) had a higher VIS and greater impairment in all subcategories. Among sighted dogs, a higher VIS was obtained in dogs with low vision compared to those with normal vision (P < 0.001). A higher VIS was associated with poorer HRQL (P < 0.001). Perfect reliability was obtained for 6/17 questions, and excellent reliability for 11/17 questions (intraclass correlation 1.0 and >0.9, respectively), and the VIS was highly responsive to therapeutic intervention (effect size 1.46). CONCLUSION: Results suggest the VIS may be clinically useful in assessing and obtaining a quantifiable measure of functional vision in dogs. Ongoing validation of the tool for clinical use is needed.

Hepatocytes direct the formation of a pro-metastatic niche in the liver.

The liver is the most common site of metastatic disease1. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver2,3. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets.

Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated 'don't-eat-me' signal.

Macrophages enforce antitumor immunity by engulfing and killing tumor cells. Although these functions are determined by a balance of stimulatory and inhibitory signals, the role of macrophage metabolism is unknown. Here, we study the capacity of macrophages to circumvent inhibitory activity mediated by CD47 on cancer cells. We show that stimulation with a CpG oligodeoxynucleotide, a Toll-like receptor 9 agonist, evokes changes in the central carbon metabolism of macrophages that enable antitumor activity, including engulfment of CD47+ cancer cells. CpG activation engenders a metabolic state that requires fatty acid oxidation and shunting of tricarboxylic acid cycle intermediates for de novo lipid biosynthesis. This integration of metabolic inputs is underpinned by carnitine palmitoyltransferase 1A and adenosine tri-phosphate citrate lyase, which, together, impart macrophages with antitumor potential capable of overcoming inhibitory CD47 on cancer cells. Our findings identify central carbon metabolism to be a novel determinant and potential therapeutic target for stimulating antitumor activity by macrophages.

Comparison of diode laser trans-scleral cyclophotocoagulation versus implantation of a 350-mm2 Baerveldt glaucoma drainage device for the treatment of glaucoma in dogs (a retrospective study: 2010-2016).

OBJECTIVE: To compare outcomes following trans-scleral cyclophotocoagulation (TSCP) and 350-mm2 Baerveldt implantation in the treatment of canine refractory glaucoma. DESIGN: Retrospective case study. CASE SELECTION: Client owned dogs undergoing surgical treatment of glaucoma within a veterinary referral hospital. PROCEDURES: Eighty-six glaucoma surgeries were performed on 83 eyes (69 dogs) diagnosed with primary or secondary glaucoma. Medical records were retrieved, and baseline data, surgery, medications, intraocular pressures (IOPs), vision, and complications were extracted. RESULTS: Fifty-four eyes (44 dogs) were treated with TSCP and placement of an anterior chamber suture shunt; 28 eyes (24 dogs) were implanted with a Baerveldt glaucoma drainage device (GDD); and four eyes (4 dogs) underwent GDD implantation after failure of TSCP to manage IOP. Following TSCP, IOP control (<20 mmHg) and vision retention occurred in 81.5% and 42.6%, respectively, for 16.1 ± 1.36 months. Following GDD implantation, 71.4% maintained IOP <20 mmHg and 69.6% maintained vision for 11.0 ± 0.94 months. IOP control without loss of vision was more likely following Baerveldt implantation (17/28; 60.7%) than TSCP (19/54; 35.2%) (P = 0.027). One eye had functional vision restored following GDD placement. IOP control without adjunctive medications was more likely following Baerveldt implantation (P = 0.02). CONCLUSIONS: In this study, eyes treated with Baerveldt GDD implantation were more likely to maintain IOP control and retain vision compared to eyes treated with TSCP and placement of an anterior chamber suture shunt. Lack of formal randomization, inconsistencies in surgical techniques and TSCP protocols, and potential unmeasured confounders must be considered when extrapolating from this retrospective study.

Intraocular sarcoma associated with lens capsule rupture and persistent hyperplastic primary vitreous in a dog.

This case report describes the clinical findings and ocular pathology in an adult Golden Retriever diagnosed with an intraocular sarcoma. Nineteen s prior to diagnosis with a lens capsule rupture and intraocular sarcoma, the dog was diagnosed with persistent hyperplastic primary vitreous and uveitis based on clinical signs and the ultrasonographic appearance of the eye. Two years after enucleation, there was no evidence of metastatic spread of the sarcoma. The immunohistochemical characteristics of the tumor as well as the limitations and supportive evidence used in attempting to identify the histogenesis of the tumor are outlined.

Kv1.3 channels facilitate the connection between metabolism and blood flow in the heart.

The connection between metabolism and flow in the heart, metabolic dilation, is essential for cardiac function. We recently found redox-sensitive Kv1.5 channels play a role in coronary metabolic dilation; however, more than one ion channel likely plays a role in this process as animals null for these channels still showed limited coronary metabolic dilation. Accordingly, we examined the role of another Kv1 family channel, the energetically linked Kv1.3 channel, in coronary metabolic dilation. We measured myocardial blood flow (contrast echocardiography) during norepinephrine-induced increases in cardiac work (heart rate x mean arterial pressure) in WT, WT mice given correolide (preferential Kv1.3 antagonist), and Kv1.3-null mice (Kv1.3-/- ). We also measured relaxation of isolated small arteries mounted in a myograph. During increased cardiac work, myocardial blood flow was attenuated in Kv1.3-/- and in correolide-treated mice. In isolated vessels from Kv1.3-/- mice, relaxation to H2 O2 was impaired (vs WT), but responses to adenosine and acetylcholine were equivalent to WT. Correolide reduced dilation to adenosine and acetylcholine in WT and Kv1.3-/- , but had no effect on H2 O2 -dependent dilation in vessels from Kv1.3-/- mice. We conclude that Kv1.3 channels participate in the connection between myocardial blood flow and cardiac metabolism.

Feline corneal sequestra: outcome of corneoconjunctival transposition in 97 cats (109 eyes).

Case series summary A retrospective study was undertaken to review outcomes of keratectomy and corneoconjunctival transposition in cats with superficial and deep corneal sequestra. Information including pertinent history, signalment, ophthalmological findings and postoperative outcome was collected from medical records. Follow-up was obtained by clinical examination, contact with the referring veterinarians and review of medical records or telephone contact with owners. Ninety-seven cats (109 eyes) were included from 2005-2015. The most commonly affected breeds included Persian, Burmese and Himalayan. The mean age at the time of surgery was 6.8 years (median 6.5 years; range 8.0 months-18.0 years). A corneal sequestrum in the contralateral eye was diagnosed in 28 cats (28.9%). Recurrent corneal sequestration was diagnosed in eight cats (nine eyes), with recurrence occurring a mean of 703 days after surgery (range 29-1750 days). Age, sex, breed, depth of sequestration and concurrent ocular disease in the contralateral eye were compared between cats with and without recurrence, with no risk factors for recurrence identified. Relevance and novel information Excellent surgical outcomes have previously been described in a series of 17 cats with superficial and mid-stromal corneal sequestra. This paper adds further information to the literature by describing a larger series of cats, with corneal sequestra affecting the full range of corneal thickness, and good long-term postoperative outcomes.

Use of a 350-mm2 Baerveldt glaucoma drainage device to maintain vision and control intraocular pressure in dogs with glaucoma: a retrospective study (2013-2016).

OBJECTIVE: To evaluate the 350-mm2 Baerveldt glaucoma drainage device (GDD) in dogs with refractory glaucoma when modifications to address postoperative hypotony (extraluminal ligature; intraluminal stent) and the fibroproliferative response (intraoperative Mitomycin-C; postoperative oral colchicine and prednisolone) are implemented as reported in human ophthalmology. DESIGN: Retrospective case series. ANIMALS: Twenty-eight client-owned dogs (32 eyes) including seven dogs (nine eyes) with primary glaucoma and 21 dogs (23 eyes) with secondary glaucoma. METHODS: The medical records of all dogs undergoing placement of a 350-mm2 Baerveldt GDD at a veterinary ophthalmology referral service between 2013 and 2016 were reviewed. Signalment, diagnosis, duration and previous treatment of glaucoma, previous intraocular surgery, IOP, visual, and surgical outcomes were recorded. RESULTS: IOP was maintained <20mmHg in 24 of 32 (75.0%) eyes. Fourteen eyes (43.8%) required no adjunctive treatments to maintain this IOP control. Fewer doses of glaucoma medication were required following surgery. Vision was retained in 18 of 27 (66.7%) eyes with vision at the time of surgery. No eyes that were blind at the time of surgery (n = 5) had restoration of functional vision. Complications following surgery included hypotony (26/32; 81.3%), intraocular hypertension (24/32; 75.0%), and fibrin formation within the anterior chamber (20/32; 62.5%). The average follow-up after placement of the GDD was 361.1 days (median 395.6 days). CONCLUSION: Efforts to minimize postoperative hypotony and address the fibroproliferative response following placement of a 350-mm2 Baerveldt GDD showed an increased success rate to other reports of this device in dogs and offers an alternative surgical treatment for controlling intraocular pressure in dogs with glaucoma.

Genetically Engineered Mouse Models of Pancreatic Cancer: The KPC Model (LSL-Kras(G12D/+) ;LSL-Trp53(R172H/+) ;Pdx-1-Cre), Its Variants, and Their Application in Immuno-oncology Drug Discovery.

Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths in the United States. For patients with unresectable disease, treatment options are limited and lack curative potential. Preclinical mouse models of PDAC that recapitulate the biology of human pancreatic cancer offer an opportunity for the rational development of novel treatment approaches that may improve patient outcomes. With the recent success of immunotherapy for subsets of patients with solid malignancies, interest is mounting in the possible use of immunotherapy for the treatment of PDAC. Considered in this unit is the value of genetic mouse models for characterizing the immunobiology of PDAC and for investigating novel immunotherapeutics. Several variants of these models are described, all of which may be used in drug development and for providing information on unique aspects of disease biology and therapeutic responsiveness. © 2016 by John Wiley & Sons, Inc.

IFNγ and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma.

UNLABELLED: Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this antifibrotic activity, though, remain unclear. Here, we report that IFNγ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C(+)CCR2(+)monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C(+)monocyte/macrophage infiltration, IFNγ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMP) in tumors, leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes, leading to enhanced chemotherapy efficacy. SIGNIFICANCE: We report that CD40 agonists improve chemotherapy efficacy in pancreatic carcinoma by redirecting tumor-infiltrating monocytes/macrophages to induce fibrosis degradation that is dependent on MMPs. These findings provide novel insight into the plasticity of monocytes/macrophages in cancer and their capacity to regulate fibrosis and modulate chemotherapy efficacy in pancreatic carcinoma.