bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A13: Development of a drug response assessment platform for biopsy-derived tumor models
Authors: Kodack David P. , Held Matthew , Damon Leah , Lee Dana , Parks Melissa , Dicecca Richard , Greenberg Max , Engelman Jeffrey A. , Benes Cyril H.
Published: March 2017

Our labs have previously described a pharmacogenomic approach to identify therapeutic strategies in cancer cells derived directly from the biopsies of patients. These findings were made in pure cancer cell populations derived on the order of months. Our ultimate goal is to utilize one's own cancer cells for a personalized in vitro diagnostic test. Therefore, we aimed to develop a reliable method to analyze a high-throughput pharmacological screen in mixed cell populations with minimal cancer cells since this is the reality of fresh samples within weeks of the biopsy. The necessity for this is two-fold: first, the culture of patient biopsies is more successful on an irradiated fibroblast feeder layer and, second, noncancerous patient cells, including stromal fibroblasts, often survive biopsy culture. We identified a cocktail of two monoclonal antibodies, one against cytokeratin 8 and another against cytokeratin 18, as a consistent identifier of lung cancer cells that could be used in a high-throughput immunofluorescence-based assay. Drug sensitivity experiments with the immunofluorescence-based assay on patient-derived lung cancer cells mixed with feeder or stromal fibroblasts produced dose-response curves consistent with a pure cancer cell viability assay. We plan to utilize this assay to test the accuracy of patient-derived tumor models, obtained within weeks of biopsy, in mimicking patients' responses to targeted therapy. Ultimately, we hope this approach could help determine therapeutic choices for individual patients.

Citation Format: David P. Kodack, Matthew Held, Leah Damon, Dana Lee, Melissa Parks, Richard Dicecca, Max Greenberg, Jeffrey A. Engelman, Cyril H. Benes. Development of a drug response assessment platform for biopsy-derived tumor models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A13.
Abstract A36: Assessment of effectiveness and molecular markers of CDK4/6 inhibitor Palbociclib in Pancreatic Ductal Adenocarcinomas
Authors: Salvador Beatriz , López-Casas Pedro P. , Menéndez Camino , Baños Natalia , Sarno Francesca , Min-Jean Yin , Olson Peter , VanArsdale Todd , Shields David J. , Hidalgo Manuel
Published: March 2017

Pancreatic Ductal Adenocarcinoma (PDAC) continues to be the deadliest human cancer with a 5-year survival rate of 7%. One of the current standards of care for advanced PDAC is gemcitabine plus nab-paclitaxel, a regimen our group helped develop. Finding new agents to combine with this regimen remains necessary, particularly using drug targeting strategies. At the molecular level, genetic and genomic profiling identified CDKN2A as a very frequently disrupted gene in PDAC (<90%). This gene encodes the tumor suppressor p16, a cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor, that controls cell cycle progression. Recently, the selective CDK4/6 inhibitor palbociclib was approved by the FDA for certain types of breast cancer patients. Whether palbociclib can also benefit patients with PDAC is unknown.

In the current study, we aimed to evaluate the effectiveness of palbociclib monotherapy and in combination with nab-paclitaxel and gemcitabine/nab-paclitaxel in a cohort of PDACs patient derived xenograft (PDX) models.

PDX models obtained from late stage PDAC patients were treated with palbociclib alone and in combination with gemcitabine/nab-paclitaxel. The majority of models displayed >50% tumor growth inhibition (TGI) following treatment with single agent palbociclib. Treatment with palbociclib plus nab-paclitaxel or palbociclib plus gemcitabine/nab-paclitaxel increased TGI to a greater degree than the gemcitabine/nab-paclitaxel combination and also increased the duration of response as compared to the standard of care therapy.

Moving forward, the palbociclib/nab-paclitaxel combination will be evaluated in a clinical trial for PDAC patients. We are currently expanding our analyses to a larger cohort of PDX models and performing molecular characterization of these models in order to gain insights on biomarkers and mechanism of action of the drug combinations in PDAC.

Citation Format: Beatriz Salvador, Pedro P. López-Casas, Camino Menéndez, Natalia Baños, Francesca Sarno, Yin Min-Jean, Peter Olson, Todd VanArsdale, David J. Shields, Manuel Hidalgo. Assessment of effectiveness and molecular markers of CDK4/6 inhibitor Palbociclib in Pancreatic Ductal Adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A36.
Abstract B30: Establishment and maintenance of a PDX Core Facility
Authors: Mattar Marissa , Uthamanthil Rajesh K. , Stanchina Elisa de
Published: March 2017

Patient Derived Xenografts (PDX) are a powerful technology with the potential to unlock key mechanisms of disease for a variety of difficult to treat cancers and cancers with no applicable laboratory models. These models have a wealth of potential applications in tumor genetics, biomarker discovery, progression of metastasis, fate of circulating tumor cells, and in drug development of novel therapies for advanced and drug-resistant tumors. While several individual laboratories can excel at establishing such models, there are challenges, both procedural and technical, which present serious obstacles for established investigators as well as new investigators without prior experience with PDX models. Therefore, for some Institutions it is preferable to designate a centralized “PDX Core” to streamline the workflow that is required for the success of such program.

Here we describe and analyze the key components of a successful Academic PDX program. The PDX coordination branch carries out administrative duties to guarantee that the multiple components involved in generating PDXs are seamlessly integrated. In particular, it deals with logistical tasks including regulatory requirements (IRB, patient consent forms, IACUC), and sample accrual (patient selection, coordination with surgery schedules, specimen collection). In addition, it takes care of database maintenance and interface with clinical applications. The PDX laboratory branch meanwhile devises and implements standard operating procedures for sample processing, storage and implantation, and model maintenance, PDX characterization and distribution, and takes care of training of specialized personnel.

The establishment of such centralized PDX core at MSKCC resulted in a tenfold increase in the Institution's ability to generate PDX models within a year of inception of the program. In particular, for ongoing projects, we observed an increase not just in sample accrual but also in tumor take rate. In addition, the number of different tumor types implanted expanded substantially, from six to over twenty.

PDXs have the potential to be invaluable tools in understanding cancer and developing novel treatments. In our experience, the establishment of a centralized PDX core is both the most cost effective and efficient way for academic investigators to generate and gain access to novel, well characterized, and clinically annotated PDX models.

Citation Format: Marissa Mattar, Rajesh K. Uthamanthil, Elisa de Stanchina. Establishment and maintenance of a PDX Core Facility. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B30.
Abstract B45: Huntsman Cancer Institute Preclinical Research Resource (PRR) Core
Authors: Smith Brittni , Kavetska Oksana , Wang Guoying , Lum David Henry
Published: March 2017

Accumulating evidence from recent genomics data has reinforced the view that tumors can display exceptional heterogeneity between patients, between tumors from the same patient and even within a single tumor. These findings, together with decades of clinical experience with varied drug responses, strongly suggest that personalized approaches to assess cancer risk and treatment will be essential to reduce mortality.

New experimental models of human tumor initiation, progression, metastasis, and therapeutic response/resistance are critical to improve cancer treatments. Current models often fail to predict the efficacy of drugs in the clinical setting. This disconnect leads to disappointing clinical trial results that do not considerably improve patient survival, to failure of the FDA to approve new therapies, and to the loss of time and money. The ideal cancer model(s) would: 1) replicate the spectrum of tumor pathologies and subtypes, 2) reproduce genetic and epigenetic alterations found in human tumors, 3) grow in the correct developmental and anatomic context, 4) have an appropriate tumor microenvironment and an intact immune system, and 5) exhibit patterns of metastasis observed in patients.

Dr. Alana Welm (HCI) has established a collection of patient-derived orthotopic breast xenografts by implanting patient tumor tissue into mice. Significant evidence demonstrates that patient-derived xenografts (PDX) recapitulate the genomic and phenotypic features of their corresponding patient tumors, and that tumor graft growth and metastasis mirrors clinical outcome in the corresponding patients. We believe that PDXs may provide a remarkable opportunity to predict the best therapy regimens for individuals, a concept termed “personalized” or “precision” medicine.

The Preclinical Research Resource (PRR) Core will provide high-quality services for basic and translational cancer research, drug discovery and personalized cancer therapy.

The mission of the core will be to: generate the most current and sophisticated patient-derived in vivo cancer models; bridge the gap between basic scientists and clinicians to facilitate seamless bench-to-bedside research; and improve pre-clinical drug efficacy evaluation and examine personalized chemotherapy with patient-derived xenografts.

Citation Format: Brittni Smith, Oksana Kavetska, Guoying Wang, David Henry Lum{Authors}. Huntsman Cancer Institute Preclinical Research Resource (PRR) Core. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B45.
Abstract IA17: Application of PDX models to pancreas cancer research
Authors: Hidalgo Manuel
Published: March 2017

Pancreatic cancer remains one of the most deadly cancers. Very few therapeutics advanced have been achieved in this disease. Over the last few years, several studies have started to elucidate the molecular biology of PDAC including the genomic landscape of the disease, the importance of the stroma and the immunesuppressive environment characteristic of PDAC. One important development in translational research in PDAC is the availability of preclinical models of the disease. This includes genetically engineered mouse models of cancer, patient derived xenografts (aka Avatar models) and organoids. These models are becoming useful for drug screening, biomarker development and personalize medicine. Using Avatar models we identified Nab-paclitaxel as an effective agent in pancreas cancer in contrast to paclitaxel that does not result antitumor effects. We also showed that Nab-paclitaxel disrupts PDAC stroma, an observation, however, has not been confirmed by others. In addition, studies in mouse models revealed the lack of predictability of SPARC expression for clinical outcome. More recently, we have identified demcizumab and palbociclib as potentially effective agents in PDX models as the basis for their clinical development. PDX models have also de potential to be used as a platform for personalizes cancer treatment. In this regard, we are now conducting the AVATAR clinical trial in which patients with advanced cancer are randomized to receive either a conventional treatment or a treatment based on integrating genomic data with AVATAR mouse mode development.

Citation Format: Manuel Hidalgo. Application of PDX models to pancreas cancer research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA17.
Abstract IA21: Opportunities for integration of PDX models into clinical trials
Authors: Kopetz Scott
Published: March 2017

Patient-derived xenograft models (PDX) provide opportunities to evaluate efficacy, pharmacodynamics, response durability, and resistance mechanisms in greater details than traditionally possible with sampling of patient tumors. When PDX models are integrated with patients enrolled in clinical trials, or treated with novel agents, there are opportunities to interrogate aspects of cancer biology not traditionally evaluable, while maintaining clinical relevance. This presentation will explore the strengths and limitations of the models, with examples on how these models are being integrated into clinical trials, validation efforts, and novel insights derived from this approach.

The concept of a co-clinical trial has been variously defined, including a definition proposed by the NCI as parallel or sequential trials of combination therapy in patients and in mouse and human-in-mouse models of appropriate genotypes to represent the patients. This concept is being extended for PDX models to incorporate tumor models derived from the same patients participating in the clinical trial, both with a goal of improving translational interrogation of the novel agent efficacy as well as emerging efforts to use the PDX models to guide patient therapy.

Validation of the PDX models for treatment response/regression will be demonstrated, including recently completed clinical trials utilizing inhibitors of BRAF and MEK with a comparison of the response of the matched PDX models to radiographic measurements from the treated patients. Cohort based validation will be demonstrated through examples with EGFR targeted therapy and comparison to randomized clinical trial results. Limitations of these approaches will be described.

PDX models from clinical trials have been demonstrated to model and replicate mechanisms of resistance in some settings, and examples from colorectal and lung cancer will be used to demonstrate this. Resistance of lung cancer to EGFR tyrosine kinase inhibitors is being explored on PDXs obtained from post-progression biopsies. Tumor heterogeneity as a mechanism of resistance has been successfully modeled in BRAF-mutant colorectal cancer, and has been integrated into prospective clinical trials.

Finally, efforts to integrate PDX models as predictors of treatment response are described. These include efforts to use matched PDX models to guide treatment decisions in patients as part of prospective clinical trials. Regulatory, logistic, and biologic limitations of such efforts will be discussed.

Citation Format: Scott Kopetz. Opportunities for integration of PDX models into clinical trials. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA21.
Abstract IA26: Conditionally Reprogrammed Cells (CRCs): A simple, two-component cell system for basic and clinical cancer research
Authors: Schlegel Richard
Published: March 2017

Conditional reprogramming (CR) is a new cell biology technique that allows for the rapid and efficient outgrowth of matched normal and tumor epithelial tissue from patient samples. This approach combines the use of a ROCK inhibitor and irradiated feeder cells to induce and select for stem-like cells from adult tissues. While normal CR cells can be maintained for prolonged periods in vitro (in most cases they are conditionally immortalized), they retain their potential to differentiate normally when returned to an appropriate in vivo or in vitro environmental niche. Tumor cells can also be readily established in culture, although they can exhibit reduced dependence upon feeder cells and ROCK inhibitor for continued proliferation. The high efficiency of this system makes it feasible to establish cell cultures from rare tumor specimens. Minor modifications of the CR method also allow for the outgrowth of neuroendocrine and mesenchyme-like cells, possibly including cells that have undergone epithelial/mesenchymal transition. Biobanking using the CR method is now standardly applied in our pathology department in order to generate a renewable resource of patient samples for scientific investigation. The greatest challenge for routine application of this method is the selection of tumor cells from surgical biopsy specimens. Since both normal and tumor cells proliferate under these conditions, it is critical to evaluate the histologic composition of the biopsies and to validate the outgrowth of tumor cells using molecular biomarkers. Modified growth conditions are being developed to facilitate the selective outgrowth of tumor cells from mixed normal/tumor samples. This cell culture system has been used to identify new therapies for rare tumors (1) and characterize patient biopsies (2), and is now being applied broadly in new NCI initiatives for second-generation cancer cell models.

1. N Engl J Med 367:1220, 2012

2. Science 346:1480, 2014

Citation Format: Richard Schlegel. Conditionally Reprogrammed Cells (CRCs): A simple, two-component cell system for basic and clinical cancer research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA26.
Abstract PR02: Humanized mouse melanoma model using patient-derived xenografts
Authors: Krepler Clemens , Perego Michela , Kalabis Mizuho , Beqiri Marilda , Hristova Denitsa , Xiao Min , Petrelli Nicholas J. , Somasundaram Rajasekharan , Herlyn Meenhard
Published: March 2017

Melanoma patients develop resistance to both chemo- and targeted-therapy drugs. Promising pre-clinical and clinical results with immune checkpoint inhibitors using antibodies directed against CTLA4 and PD1 have re-energized the field of immune-based therapies in melanoma. However, similar to chemo- or targeted-therapies only subsets of melanoma patients respond to immune checkpoint blockade. Currently available immunodeficient mouse xenograft and transgenic mouse melanoma models have a number of short comings and are unable to address the basis of drug resistance and immune non-responsiveness frequently observed in melanoma patients treated either with chemo- and targeted-therapy drugs or immune checkpoint inhibitors. Thus there is an urgent need to establish a mouse model with an immune microenvironment that can address the above issues encountered in melanoma patients. For this, our laboratory has developed a humanized mouse melanoma model using patient-derived xenograft (PDX). Immunodeficient (NOD/Shi-SCID/IL-2Rgnull [NOG; Taconic]/ NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ [NSG; Jackson Laboratory]) mice were reconstituted with human CD34+ cells and after 12 weeks, mature human CD45+ cells are observed in mouse peripheral blood and in the lymphoid organs. Humanized mice with optimum number of mature human CD45+ cells in peripheral blood were challenged with HLA-matched melanoma PDX and the immune response to melanoma associated antigens were monitored. Lymphoid cells derived from humanized mice that are challenged with human leukocyte antigen (HLA) matched melanoma cells in vivo showed enhanced cytokine expression to in vitro stimulation with peptides derived from melanoma antigens. In addition, cytotoxic T-cells were able to functionally lyse tumor cells in vitro, infiltrate and restrict in vivo tumor growth. We are currently refining our model to establish an autologous mouse melanoma model. Our innovative humanized mouse melanoma model will enable one to understand the causes of therapy resistance and immune non-responsiveness in patients.

This abstract is also being presented as Poster B33.

Citation Format: Clemens Krepler, Michela Perego, Mizuho Kalabis, Marilda Beqiri, Denitsa Hristova, Min Xiao, Nicholas J. Petrelli, Rajasekharan Somasundaram, Meenhard Herlyn. Humanized mouse melanoma model using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR02.
Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients
Authors: De Velasco Guillermo , Je Youjin , Bossé Dominick , Awad Mark M. , Ott Patrick A. , Moreira Raphael B. , Schutz Fabio , Bellmunt Joaquim , Sonpavde Guru P. , Hodi F. Stephen , Choueiri Toni K.
Published: March 2017

Immune-related adverse events (irAE) have been described with immune checkpoint inhibitors (ICI), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab, or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6,528 received an ICI (nivolumab, 1,534; pembrolizumab, 1,522; atezolizumab, 751; and ipilimumab, 2,721) and 4,926 had not. Compared with non-ICI arms, ICIs were associated with more all-grade colitis (RR 7.66, P < 0.001), aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020), rash (RR 2.50; P = 0.001), hypothyroidism (RR 6.81; P < 0.001), and pneumonitis (RR 4.14; P = 0.012). Rates of high-grade colitis (RR 5.85; P < 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms. Ipilimumab was associated with a higher risk of all-grade rash (P = 0.006) and high-grade colitis (P = 0.021) compared with PD-1/PD-L1 ICIs. Incidence of fatal irAE was < 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications. Cancer Immunol Res; 5(4); 312–8. ©2017 AACR.
Abstract A03: A role for Macrophage Migration Inhibitory Factor (MIF) in breast cancer growth and metastasis
Authors: Balogh Kristen N. , Cross Janet V.
Published: March 2017

The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that has been well-characterized as a mediator of numerous inflammatory disease processes. We have previously demonstrated that expression of MIF in the primary tumor promotes growth and metastasis in the 4T1 murine model of breast cancer. MIF is overexpressed in many cancer types, including breast cancer, and the degree of MIF expression correlates with tumor aggressiveness. We therefore sought to understand the link between primary tumor expression of MIF and increased tumor growth and metastasis. As a cytokine, we hypothesized that MIF would function by controlling some aspect of the interaction between tumor and host immune system. This was supported by our observation that MIF expression was no longer required for growth and metastasis in an immunodeficient SCID/bg host. Using flow cytometry, we discovered that MIF expression in the primary tumor decreased the abundance of intra-tumoral CD8+ T cells, as well as inhibited those cells' ability to produce the cytokine IFNgamma. We also found that depletion of T cells from MIF KD tumor bearing mice restored tumor growth to the level of WT tumors, while this depletion had no effect on the growth of WT tumors. This suggests that T cells are playing an important role in the control of tumor growth seen in MIF KD tumors. Previous work in the lab has also shown that MIF expression in the primary tumor increased the abundance of an immunosuppressive cell subset known as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We hypothesize that this population of cells is responsible for the reduced T cell infiltration and activity seen MIF-expressing tumors, and we aim to determine the mechanisms by which MIF promotes MDSC accumulation and/or function, and how the MDSCs are inhibiting T cell activity in the tumor.

Citation Format: Kristen N. Balogh, Janet V. Cross. A role for Macrophage Migration Inhibitory Factor (MIF) in breast cancer growth and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A03.
Abstract A05: Biphasic anti-tumoral effect of a vascular-disrupting agent triggering STING and tumor regression
Authors: Weiss Julia M. , Guerin Marion , Regnier Fabienne , Thoreau Maxime , Peranzoni Elisa , Feuillet Vincent , Renault Gilles , Guilbert Thomas , Trautmann Alain , Bercovici Nadege
Published: March 2017

Despite significant advances, cancer immunotherapies fail to systematically elicit tumor regression. It is therefore crucial to understand what conditions the efficacy of immune responses against solid tumors. In particular, while the involvement of T lymphocytes does not need to be further proven, their relative contribution and their cooperation with other cells in regressing tumors is still ill defined. We have investigated in a breast tumor model (PyMT-MMTV) the dynamics of the immune response which takes place during the tumor regression induced by a single i.p. injection of DMXAA, a ligand and activator of STING (a key detector of cytoplasmic DNA and of viral infection). We have shown that the DMXAA-induced tumor vascular disruption, visualized by contrast-enhanced ultrasound, and the associated IFNα/β release, conditioned a swift and massive recruitment of neutrophils, followed by a delayed rise in CD8 T cells and inflammatory monocytes in the tumor mass. All these immune cell subsets contributed to the efficacy of tumor regression, as evidenced by in vivo depletion experiments, which, together with dynamic imaging allowed to characterize cooperations between these immune cell subsets. We have analyzed the kinetics of the biphasic effect of DMXAA : vascular disruption followed by an anti-tumoral immune response. These data support the idea that the inflammation in the tumor microenvironment can be modulated to reset immune cell cooperation like in an acute phase of an immune response against foreign pathogens.

Note: This abstract was not presented at the conference.

Citation Format: Julia M. Weiss, Marion Guerin, Fabienne Regnier, Maxime Thoreau, Elisa Peranzoni, Vincent Feuillet, Gilles Renault, Thomas Guilbert, Alain Trautmann, Nadege Bercovici. Biphasic anti-tumoral effect of a vascular-disrupting agent triggering STING and tumor regression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A05.
Abstract A08: Dectin-1 signaling drives pancreatic oncogenesis by promoting adaptive immune suppression
Authors: Daley Donnele , Akkad Neha , Mohan Navyatha , Ochi Atsuo , Werba Gregor , Mani Vishnu , Barilla Rocky , Zambirinis Constantinos , Hundeyin Mautin , Lee Ki Buom , Chang Steven , Wang Ding , Gardener Lawrence , Ueberheide Beatrix , Miller George
Published: March 2017

Progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intra-tumoral immune tolerance are uncertain. Dectin-1 is an innate immune receptor critical in anti-fungal immunity, but its role in sterile inflammation and oncogenesis is not well-defined. Further, non-pathogen-derived ligands for Dectin-1 have not been characterized. We found that Dectin-1 is highly expressed on myeloid cells in pancreatic ductal adenocarcinoma (PDA). Moreover, Dectin-1 ligation accelerates PDA, whereas Dectin-1 deletion, or blockade of its downstream signaling, was highly protective. We show that Dectin-1 ligates the lectin Galectin-9 in the PDA tumor microenvironment (TME) leading to macrophage-induced adaptive immune suppression. Upon interruption of the Dectin-1–Galectin-9 axis, CD4+ and CD8+ T cells – which are dispensable to PDA progression in hosts with an intact signaling axis – become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that Dectin-1 and Galectin-9 are novel and attractive targets for PDA immunotherapy.

Citation Format: Donnele Daley, Neha Akkad, Navyatha Mohan, Atsuo Ochi, Gregor Werba, Vishnu Mani, Rocky Barilla, Constantinos Zambirinis, Mautin Hundeyin, Ki Buom Lee, Steven Chang, Ding Wang, Lawrence Gardener, Beatrix Ueberheide, George Miller. Dectin-1 signaling drives pancreatic oncogenesis by promoting adaptive immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A08.
Abstract A24: Evaluation of the expression of immune functional markers in the tumor microenvironment
Authors: Kim Jeffrey , Li Na , He Mingxiao , Zhang Bingqing , Su Nan , Ma Xiao-Jun , Park Emily
Published: March 2017

Recent clinical successes with immune checkpoint blockades have provided promising immune-based therapeutic approaches for controlling malignancy. While therapeutic antibodies against CTLA-4 and PD-1/PD-L1 have resulted in potent and durable clinical responses in many patients, there still remains an urgent need to develop biomarker based assays to identify patients who may benefit from these approaches while avoiding toxicity and without compromising efficacy. While gene and protein expression of immune cell and checkpoint markers can be obtained through traditional techniques, insight regarding spatial and cell-specific expression within the tumor microenvironment is lacking, particularly in regards to secreted proteins with key immune functions. RNAscope® is an advanced in situ hybridization assay that allows for the visualization of single-cell gene expression, targeting mRNA sequences directly in tissues. The probes designed for this approach permit the detection of secreted markers, including cytokines and chemokines. In our investigation of 60 archived formalin-fixed paraffin embedded non-small cell lung cancer biopsies, expression profiles of immune checkpoint markers and immune functional molecules were evaluated in the tissue environment by RNAscope®. Each of the tumors displayed distinct co-expression patterns of immune checkpoint markers as well as varying levels of cytokines (TGFβ, IFNγ, and TNFα) and chemokines, which were measured in respect to their relative location in the tumor or stromal regions. Additionally, the detection of immune cell markers were used to pinpoint the location of infiltrating lymphocytes. The methods and findings in this study provide a valuable glimpse into the understanding of key immune functional markers in the tumor microenvironment to potentially advance treatment opportunities in this era of immuno-oncology therapies.

Citation Format: Jeffrey Kim, Na Li, Mingxiao He, Bingqing Zhang, Nan Su, Xiao-Jun Ma, Emily Park. Evaluation of the expression of immune functional markers in the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A24.
Abstract A39: Cholangiocarcinoma-exposed cytokine-induced killer cells developed senescence and exhaustion
Authors: Wongkajornsilp Adisak , Sawatpiboon Nathawadee , Duangsa-ard Sunisa , Kasetsinsombat Kanda , Maneechotesuwan Kittipong , Hongeng Suradej
Published: March 2017

The existence of cellular exhaustion and senescence have been well-documented in T cells, but not yet in CIK cells. The exposure of CIK cells to HubCCA1 cholangiocarcinoma cells resulted in sustaining the proportion of CD3+CD56+ subset at the expense of that of the pure T cell (CD3+CD56-) subset. All major subsets (CD3+CD56+, T cell subsets, and NK cell (CD3-CD56+ subset) of the survived CIK cells were inflicted with increasing senescence markers (KLRG1, CTLA4, and CD57) upon the exposure length. However, CD28, a T cell activation marker, was up-regulated in CD3+CD56+ and NK cell subsets upon tumor exposure, but was suppressed in T cell subset. The co-culture of CIK cells with dendritic cells (DCs) could alleviate CD57, but not KLRG1 nor CTLA4. For exhaustion, the co-culture with DCs could lower the level of PD-1 in CD3+CD56+ and T cell subset, but was unable to withstand the massive up-regulation of PD-1 and Tim-3 in all 3 major subsets upon the tumor exposure. The co-culture with DCs raised the proportion of Treg (CD4+CD25+Foxp3+) subset in CIK cells, but surprisingly reversed by the eventual exposure to tumor cells. In summary, the exposure of CIK cells to tumor cells rendered the development of senescence and exhaustion to the CIK cells. The co-culture of CIK cells with DCs had limited role in preventing these opposing effects.

Citation Format: Adisak Wongkajornsilp, Nathawadee Sawatpiboon, Sunisa Duangsa-ard, Kanda Kasetsinsombat, Kittipong Maneechotesuwan, Suradej Hongeng. Cholangiocarcinoma-exposed cytokine-induced killer cells developed senescence and exhaustion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A39.
Abstract A40: Class IIa HDAC inhibition promotes an anti-tumor macrophage phenotype that induces breast tumor regression and inhibits metastasis
Authors: Guerriero Jennifer L. , Sotayo Alaba , Ponichtera Holly , Pourzia Alexandra , Schad Sara , Carrasco Ruben , Suzan Lazo , Bronson Roderick , Letai Anthony
Published: March 2017

While tumor-associated macrophages (TAMs) often have net pro-tumor effects, their embedded location and their untapped potential provide impetus to the discovery of strategies to turn them against tumors. We recently reported that a first in class selective class IIa HDAC inhibitor (TMP195) influenced human monocyte responses to colony stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumor microenvironment and reduces tumor burden and pulmonary metastases through macrophage modulation. TMP195 induces recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumors. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumor reduction. These data introduce class IIa HDAC inhibition as a novel means to harness the anti-tumor potential of macrophages to enhance cancer therapy.

Citation Format: Jennifer L. Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Lazo Suzan, Roderick Bronson, Anthony Letai. Class IIa HDAC inhibition promotes an anti-tumor macrophage phenotype that induces breast tumor regression and inhibits metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A40.
Abstract B31: IRAK-4 signaling in melanoma contributes to reduced expression of inflammatory factors in vitro while contributing to tumor growth in vivo
Authors: Lasola Jackline Joy Martin , Geng Degui , Shrestha Rojesh , Davila Eduardo
Published: March 2017

An underlying and universal hindrance to T-cell-based cancer therapies is the development of immunosuppressive mechanisms that in large part originate from the persistent expression of inflammatory factors. Understanding the fundamental mechanisms that regulate chronic inflammation and targeting of this pathway(s) is critical for developing effective strategies to restore anti-tumor T-cell activity. We recently reported that the IL-1 receptor associated kinase-4 (IRAK-4) is over-expressed and activated in most melanoma cases. IRAK-4 is a central kinase in the inflammatory process that regulates the expression of various inflammatory and immunosuppressive molecules. Inhibiting IRAK-4 activity in melanoma drastically reduced the expression of various inflammatory factors in vitro. Furthermore, IRAK-4 signaling in melanoma contributed to tumor growth in vivo and was associated with an increased frequency of phenotypically exhausted (PD1+Lag3+) tumor infiltrating T-cells, myeloid derived suppressor cells, and a trend toward higher numbers of CD4+ T regs. Ongoing studies are focused on testing the hypothesis that targeting IRAK-4 signaling in tumor cells will alter the expression of inflammatory factors in the tumor environment which will reduce immunosuppression and sensitize melanoma to T-cell-mediated killing.

Citation Format: Jackline Joy Martin Lasola, Degui Geng, Rojesh Shrestha, Eduardo Davila. IRAK-4 signaling in melanoma contributes to reduced expression of inflammatory factors in vitro while contributing to tumor growth in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B31.
Abstract B38: Non-cytotoxic effects of the chemotherapeutic agent gemcitabine can alter the immunophenotype of tumor cells in in vitro culture
Authors: Gravett Andrew M. , Copier John P. , Liu Wai M. , Cranage Martin P. , Dalgleish Angus G.
Published: March 2017

In addition to their cytotoxic/cytostatic properties, some chemotherapeutics have shown a remarkable capacity to modulate immune response. One such chemotherapy is the antimetabolite, gemcitabine (GEM). GEM has been shown to influence the quantity and activation of certain immune cell subsets when used in vivo. It has also been demonstrated that administration of GEM in conjunction with immunotherapy, such as dendritic cell vaccination, is beneficial in terms of overall survival and progression-free survival. The purpose of this study is to investigate if GEM can influence the way that tumor cells surviving treatment are regarded by the immune system. Our group has found that short-term in vitro culture with GEM enhances expression of human leukocyte antigen (HLA) class I, CD95, NKG2D ligands and TRAIL receptors on tumor cell lines. These molecules are all cell surface proteins important for the efficient surveillance and effector function of the immune system. The HLA class I increase is beta-2-microglobulin dependent and changes are underpinned by ERK, JNK and RelB-NFkB signalling pathways. Furthermore, culture with GEM induces immunoproteasomal components LMP2 and MECL-1 in tumor cells and, subsequently, the peptide antigen repertoire displayed on HLA class I is altered. The changes in peptide characteristics include amino acid anchor residue modifications which render the peptides likely to favor binding alternative HLA-allotypes. The renovation of the peptidome displayed by HLA class I may reveal sub-dominant immunogens to T-cells. Taken together, these changes may render tumor cells more sensitive to immune cell-mediated lysis. These data help explain observations made in previous in vivo studies, advise as to which novel antigens could be utilised in future vaccination protocols and lend further credence to the idea that chemotherapy and immunotherapy could be used in combination.

Citation Format: Andrew M. Gravett, John P. Copier, Wai M. Liu, Martin P. Cranage, Angus G. Dalgleish. Non-cytotoxic effects of the chemotherapeutic agent gemcitabine can alter the immunophenotype of tumor cells in in vitro culture. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B38.
Abstract B55: The alarmin IL-33 is expressed in breast cancer: An emerging role in breast cancer immunity via the activation of NK cells?
Authors: Blanc Elena , Eberhardt Anais , Herbulot Jennifer , Beux Céline Le , Colombe Amelie , Morel Anne-Pierre , Saintigny Pierre , Charrier Emilie , Marcais Antoine , Treilleux Isabelle , Walzer Thierry , Caux Christophe , Bendriss-Vermare Nathalie
Published: March 2017

Interleukin (IL)-33 is an alarmin belonging to the IL-1 family. Through its receptor ST2, IL-33 promotes both type 1 and type 2 immune responses depending on i) the type of responding cells and ii) the microenvironment in damaged tissues. Paradoxical roles of IL-33 have been reported in the context of cancer. Indeed, experimental models of murine mammary carcinoma and clinical observations from breast cancer (BC) patients suggest a protumoral role for IL-33, while antitumor effects of IL-33 via T cell and NK cell activation have also been described in mice. These observations prompted us to revisit the role of IL-33/ST2 axis in BC immunity by investigating the expression of IL-33 in tumors and its impact on Natural Killer (NK) cells biology, which exert anti-tumoral properties via cytokine production and cytotoxic function. Using immunohistochemistry (IHC) as well as mRNA expression analyses (RTqPCR or in silico analyses using public transcriptomic datasets from human breast tumors), we observed that IL-33 is expressed at higher levels in i) Ductal carcinoma in situ (DCIS) compared to invasive breast cancer (IBC), especially in the stroma and ii) triple-negative BC. In situ, IL-33 was found to be expressed in endothelial cells and scattered cells within the stroma of breast tumors. Furthermore, we showed that IL-33, in combination with IL-12, i) potentiates greatly the production of IFN-γ (x1000) by NK cells, in an ST2-dependent manner, ii) induces CD25 and CD69 on their surface, iii) stimulates intracellular NFκB/p38MAPK/mTOR signaling pathways, and iii) increases their natural cytotoxicity towards K562 target cells as well as their proliferation. Importantly, we have some evidence that IL-33 activates a subset of CD56intermediate NK cells. Altogether, our observations are in favor of an NK-mediated antitumor role of IL-33 in cancer that we are currently investigating in a mouse tumor model in vivo.

Citation Format: Elena Blanc, Anais Eberhardt, Jennifer Herbulot, Céline Le Beux, Amelie Colombe, Anne-Pierre Morel, Pierre Saintigny, Emilie Charrier, Antoine Marcais, Isabelle Treilleux, Thierry Walzer, Christophe Caux, Nathalie Bendriss-Vermare. The alarmin IL-33 is expressed in breast cancer: An emerging role in breast cancer immunity via the activation of NK cells? [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B55.
Abstract B65: Alteration in cholesterol homeostasis and antibody synthesis in B cells an in-vivo effect of carcinogen (polyaromatic)
Authors: Saxena Nimisha , Kaur Amar Preet , Chandra Nimai Chand
Published: March 2017

Introduction: Cholesterol, a major ingredient of cellular growth, is maintained in the cells by either intracellular biosynthesis or LDL receptor mediated endocytosis. Various studies have shown increased LDLR and SREBP2 (transcription factor) expressions as well as intracellular saturation of cholesterol in malignant and proliferating cells.

Objectives: Citation of immune suppression is common in malignancy. B cells are antibody forming immune cells. Fate of Benzo-alpha-pyrene (mitogenic and carcinogenic doses) on B-cells has been aimed by exploring the role of cellular cholesterol homeostasis.

Methods: Intraperitoneal injection of carcinogen, classical mitogen and immunogen to Swiss Albino mice in groups for optimally effective dose, B-cell (CD19 & CD79a) counts by flowcytometry, ELISA for IgG estimation, western blot for protein expressions and spectrophotometry for cholesterol estimation were among the parameters studied.

Results: At immunosuppressive dose of Benzo-alphapyrene a significant decrease in serum IgG level, no significant change in number of B lymphocytes as compared with other agents, depressed expressions for LDLR / SREBP2 and significant decrease of cellular cholesterol (cytosolic and nuclear) were observed in mice model system.

Conclusion: Benzo-alphapyrene leads to decrease in LDLR and SREBP2 expression resulting insufficient total intracellular cholesterol level and thus affects B-cell to proliferate. Immunosupression becomes apparent, which allows carcinogen to stay in the system and generation of tumor elsewhere.

Citation Format: Nimisha Saxena, Sr., Amar Preet Kaur, Sr., Nimai Chand Chandra. Alteration in cholesterol homeostasis and antibody synthesis in B cells an in-vivo effect of carcinogen (polyaromatic). [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B65.
Abstract IA06: Role of TCR specificity in regulatory T cell selection
Authors: Hsieh Chyi-Song
Published: March 2017

Regulatory T (Treg) cells play an important role in preserving self-tolerance and preventing autoimmunity. Because of this, Treg cells generate a natural barrier to immune mediated tumor rejection. Here, we will discuss the process of thymic education that generates a self-reactive Treg cell population which can suppress both autoimmune and anti-tumor responses. Treg cell selection in the thymus is primarily mediated by antigen-presenting cells (APCs) in the medulla, including medullary thymic epithelial cells (mTECs) that express the transcription factor Aire, as well as bone marrow (BM) APCs such as dendritic cells (DCs). Using TCR repertoire analysis of fixed TCRβ chain mice, we recently reported that BM APCs and mTECs make substantial contributions to negative and Treg cell selection. Interestingly, Aire-dependent TCRs were often dependent on BM APC antigen presentation, even though Aire expression itself is restricted to mTECs. Analysis of a selected set of Aire- and BM APC co-dependent TCRs suggests that Batf3-dependent CD8α+ DCs are the major BM APC subset responsible for co-operative antigen presentation. We will also discuss TCR repertoire analyses of Batf3/mice deficient in CD8α+ DCs, as well as potential mechanisms of antigen-transfer from mTECs to DCs and the implications on Treg cell recognition of self-antigens.

Citation Format: Chyi-Song Hsieh. Role of TCR specificity in regulatory T cell selection. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA06.