bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A42: MK-1775, a WEE1 inhibitor alleviates resistance to immune attack of tumor cells undergoing an epithelial-mesenchymal transition
Authors: Hamilton Duane H. , Fernando Romaine I. , Tsang Kwong-Yok , Palena Claudia
Published: October 2015

The phenomenon of epithelial-mesenchymal transition (EMT) is a phenotypic switch that allows epithelial tumor cells to acquire features of mesenchymal cells, including the ability to migrate and invade and, therefore, to disseminate from the primary site. In addition to promoting tumor dissemination, various reports have demonstrated that acquisition of features of EMT associates with tumor resistance to the cytotoxic effects of chemotherapy, radiation, and some targeted therapies. It is not well understood, however, the contribution of EMT to the escape of tumors from host immune-surveillance and immune-mediated rejection. Our laboratory has characterized the T-box transcription factor brachyury as a tumor-associated antigen and a regulator of EMT in human carcinomas. By generating isogenic cancer cell lines with various levels of brachyury expression, we demonstrated that high levels of brachyury significantly reduce the susceptibility of cancer cells to lysis by both antigen-specific T cells and natural killer cells, and render tumor cells less responsive to a cancer vaccine in syngeneic murine tumor models. This resistance was due to inefficient caspase-dependent apoptosis, manifested as inefficient nuclear lamin degradation in the presence of activated effector caspases. We correlated this phenomenon to loss of cell cycle kinase CDK1, which mediates lamin phosphorylation. In support of a causal connection, pre-treatment of tumor cells with MK-1775, a specific inhibitor of WEE1, which is known to be a negative regulator kinase of CDK1 activity, could counter the defective apoptosis of tumor cells expressing high levels of brachyury. Thus, our findings suggest reconstituting CDK1 activity to threshold levels might be sufficient to elevate immune-mediated lysis of mesenchymal-like cancer cells, and improve the efficacy of anti-tumor vaccines.

Citation Format: Duane H. Hamilton, Romaine I. Fernando, Kwong-Yok Tsang, Claudia Palena. MK-1775, a WEE1 inhibitor alleviates resistance to immune attack of tumor cells undergoing an epithelial-mesenchymal transition. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A42.
Abstract A81: Immune-cancer interactions in tumors and tumor-draining lymph nodes: Novel prognostic indicators for breast cancer
Authors: Mansfield James , Lee Peter
Published: October 2015

It is becoming clear that immune cells play many important but sometimes conflicting roles in cancer., and iImmune profile changes at sites of immune–cancer interactions, such as the tumor microenvironment and tumor-draining lymph nodes (TDLNs), may represent a sensitive predictor of local and distant tumor metastasis. However, standard pathologic analysis of tumor sections has remained at the visual assessment of one marker per serial section level; it would be extremely useful to be able to visualize the distributions of multiple phenotyped immune and other cells in-situ in solid tumors to dissect the complex interplay between immune/stromal cells and cancer cells within tumors, tumor-draining lymph nodes (TDLNs), and blood. We generate immune profiles that include complete immunophenotyping and identification of cellular spatial relationships within and between the tumor microenvironment and TDLNs from formalin-fixed paraffin-embedded lymph node and tumor specimens from cancer patients using a combination of multiplexed IHC/IF, multispectral imaging, and automated image analysis which delivers quantitative per-cell measures of each marker. These per-cell intensities are then translated into a phenotype for each cell. We have found that immune cell populations as well as their spatial distributions and clustering patterns have strong correlation with clinical outcome.

Citation Format: James Mansfield, Peter Lee. Immune-cancer interactions in tumors and tumor-draining lymph nodes: Novel prognostic indicators for breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A81.
Abstract A85: Identification and enrichment for rare naturally occurring tumor-reactive T cells in the tumor microenvironment reveals new and diverse opportunities for cancer immunotherapy
Authors: Powell Daniel J.
Published: October 2015

The existence of naturally-occurring, tumor-reactive T-cells in human cancer has rationalized the application of immunotherapy in oncology, however the immunobiology of spontaneous tumor-reactive T-cells in cancer is not well-defined due to difficulties in identifying and validating these responses. The ability to identify and characterize rare tumor-reactive T cells has strong prognostic value and holds the potential to enable various forms of immunotherapy, including adoptive T cell therapy, TCR gene therapy and immune checkpoint inhibition. In our attempt to explore the immunobiology of naturally-occurring immune responses in patients, we have now elucidated CD137 as a biomarker for bona fide naturally-occurring, tumor-reactive T-cells in cancer and developed a rapid, accurate system to comprehensively isolate tumor infiltrating lymphocytes (TILs) with tumor-rejecting capability directly from resected tumors. CD137+ TILs from various tumor types recognized autologous and HLA-matched tumor in an HLA-restricted manner, resulting in proflammatory cytokine production and cancer killing in vitro, and tumor growth inhibition in vivo; CD137-negative TILs did not. More so, multiparameter phenotyping of the CD137+ TIL subset revealed a vast network of expressed negative immunoregulatory molecules and opportunities for immune checkpoint inhibition. Our findings implicate a role for CD137 in the immunobiology of human cancer where it is preferentially expressed on the tumor-reactive TIL subset, and provides a new roadmap for the rational design of cancer immunotherapy trials.

Citation Format: Daniel J. Powell, Jr. Identification and enrichment for rare naturally occurring tumor-reactive T cells in the tumor microenvironment reveals new and diverse opportunities for cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A85.
Abstract B05: A biologic screen to evaluate potential toxicity of chimeric antigen receptor modified T cells against primary normal human tissues
Authors: Cogdill Alexandria P. , Boesteanu Alina , Haines Kathleen , Fraietta Joseph , Scholler John , Loew Andreas , Thekkat Pramod , Brogdon Jennifer , Maus Marcela V. , June Carl , Johnson Laura A.
Published: October 2015

Adoptive cell therapy with chimeric antigen receptor (CAR) engineered T lymphocytes has recently shown great success for the treatment of hematologic malignancies. Similar strategies based on enhancing T cell function and redirecting these lymphocytes against solid tumors are being developed, however, early attempts have resulted in unexpected toxicity of normal cells expressing shared antigen or cross-reactive antigens. A primary challenge in translating new CARs to therapeutic platforms is the lack of robust models to predict potential adverse events pre-clinically. To address this challenge, we developed an in vitro system consisting of thirteen expanded primary human cell types. To detect potential off-tumor on-target effects on normal tissues, we co-cultured CARs directed against human epidermal growth factor receptor (EGFR) in our primary cell panel. Flow cytometric and chromium release assays were used to measure intracellular cytokine production by effectors and specific cell lysis of targets, respectively. T cells expressing a CAR against wild-type EGFR elicited strong effector cytokine production and effectively lysed both tumor and normal cells expressing EGFR. In contrast, T cells engineered to express a humanized CAR against mutant EGFR variant III (EGFRvIII), a tumor-specific antigen, reacted only with tumors and did not react to the panel of primary cell targets. This demonstrated a lack of potential cross-reactivity related to off-tumor on-target effects in the normal cell types represented here, suggesting improved safety for clinical use. The thirteen primary cell types we have generated form a panel of normal cells to test novel CAR T cells for potential toxicity and an adequate therapeutic index prior to first-in-human studies.

Citation Format: Alexandria P. Cogdill, Alina Boesteanu, Kathleen Haines, Joseph Fraietta, John Scholler, Andreas Loew, Pramod Thekkat, Jennifer Brogdon, Marcela V. Maus, Carl June, Laura A. Johnson. A biologic screen to evaluate potential toxicity of chimeric antigen receptor modified T cells against primary normal human tissues. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B05.
Abstract B06: Imaging regulatory mechanisms that limit intratumoral CTL function in a mouse melanoma model
Authors: Feferman Tali , Zabolinsky Natalia G. , Manaster Yoav , Hutzler Anat , Shakhar Guy
Published: October 2015

Introduction: Immunotherapies that harness CTLs to eradicate solid tumors, melanoma in particular, have re-emerged as potent clinical options in recent years. Improving the dispersion and cytotoxicity of intratumoral CTLs may further benefit patients. To gain insight into the regulatory processes that limit CTL activity in melanoma we investigated the influence of PD-1 signaling and Tregs on CTL behavior.

Methodology: To mimic adoptive cell therapy we transferred mice bearing B16.OVA melanoma tumors with OT-I CTLs. To study Treg-mediated regulation, we used FOXP3-GFP-LuciDTR-4 host mice, in which 95% of the cells expressing Foxp3 could be depleted using diphtheria toxin. To study PD-1 mediated regulation we injected anti PD-1 to WT host mice. Tumor rejection was monitored for 2-5 weeks.

Two-photon imaging of live mice was used to follow the behavior of CTLs and Tregs within tumors. Time-lapse confocal microscopy was used to follow the influence of PD-1 signaling on the behavior of CTLs and their interaction with B16-Ova cells.

Results: Tumor rejection was closely regulated by Tregs as tumors were densely infiltrated by these cells and their depletion dramatically accelerated tumor rejection. Interactions between CTLs and Tregs seemed indirect, as they did not form conjugates. Following their transfer, antigen-specific OT-I CTLs, as well as polyclonal CTLs, entered murine tumors through selected ICAM-decorated intratumoral vessels. As CTLs accumulated, Treg numbers in the tumors dropped and CTLs could be observed conjugating tumor cells and killing them. Treatment with anti PD-1 increased CTL velocities and accelerated killing of B16.OVA cells in vitro, and was mirrored in vivo by enhanced tumor rejection.

Whereas CTL migration and cytolysis was limited to oxygenated tumor areas within 50 µm of flowing blood vessels, Tregs exhibited higher velocities, were not affected by the proximity of blood vessels, and penetrated deeper into avascular areas.

Conclusions: Our findings suggest that regulatory mechanisms influence CTL efficiency partly by affecting their migration. CTLs, more than Tregs, depend on oxygen for intratumoral locomotion and cytolysis. This disparity allows tumor cells to escape CTL lysis in deep hypoxic tumor niches where high Treg to CTL ratios favor their survival. Thus, differential motility and dependence on oxygen among CTLs and Tregs can dictate the efficiency of CTL-based therapies of melanoma.

Citation Format: Tali Feferman, Natalia G. Zabolinsky, Yoav Manaster, Anat Hutzler, Guy Shakhar. Imaging regulatory mechanisms that limit intratumoral CTL function in a mouse melanoma model. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B06.
Abstract B08: Invariant NKT cells as a platform for cancer immunotherapy with chimeric antigen receptors
Authors: Heczey Andras , Liu Daofeng , Tian Gengwen , Marinova Ekaterina , Gao Xiuhua , Guo Linjie , Hicks John , Dotti Gianpietro , Metelitsa Leonid
Published: October 2015

Advances in the design of chimeric antigen receptors (CARs) have improved the anti-tumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells and their restriction by polymorphic HLA molecules limit their therapeutic potential and are associated with toxicity, especially in allogeneic settings. We proposed that CAR expression in Vα24-invariant NKT cells (NKTs) can build upon the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKTs were engineered to express a CAR against the GD2 ganglioside, which is highly expressed by neuroblastoma. We compared CAR constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB co-stimulatory endodomains. CAR expression rendered NKTs highly cytotoxic against neuroblastoma cells without affecting their TCR-induced proliferation and CD1d-dependent killing of M2-polarized macrophages. We observed a striking Th1-like polarization of NKTs by 4-1BB-containing CARs in vitro and in mice. Expression of both CD28 and 4-1BB endodomains in the CAR maximized persistence of NKTs in NSG mice with neuroblastoma xenografts. These NKTs, expressing CAR with two co-stimulatory endodomains localized to the tumor site more effectively than T cells with the same CAR (p < 0.001). Three weekly injections of 107 CAR NKTs prolonged survival of humanized (hu)NSG mice with metastatic neuroblastoma (75.2 ± 6 days) compared to a single injection (52.1 ± 4.3 days, p = 0.007) or untreated control (35.4 ± 1.2 days, p < 0.0001). A single injection of CAR T cells was associated with tumor regression early after treatment but resulted in lethal graft-versus-host disease (GvHD) within 5 weeks that prevented evaluation of the anti-tumor activity. In contrast, CAR NKTs did not induce GvHD, even after repeated injections. These results establish the potential of NKTs to serve as a safe and effective platform for CAR-directed cancer immunotherapy.

Citation Format: Andras Heczey, Daofeng Liu, Gengwen Tian, Ekaterina Marinova, Xiuhua Gao, Linjie Guo, John Hicks, Gianpietro Dotti, Leonid Metelitsa. Invariant NKT cells as a platform for cancer immunotherapy with chimeric antigen receptors. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B08.
Abstract B12: Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptor
Authors: O'Brien Shaun , Thomas Rajan M. , Albelda Steven M. , Wells Andrew D. , Wang Liang-Chuan S.
Published: October 2015

Recent success of adoptive transfer of T cells expressing chimeric antigen receptors (CARs) in patients with blood-borne malignancies has resulted in growing enthusiasm to apply the same approach to treat solid tumors. CAR-expressing T cells, however, will likely face many challenges that will limit their efficacy in solid tumors. One possible obstacle will be the intrinsic negative feedback system that prevent continuing T cell responses. The transcription factor Ikaros, which has been shown to suppress endogenous T effector functions through epigenetic remodeling of cytokine gene loci, may be one such negative regulator. Here we show that anti-mesothelin CAR (mesoCAR) T cells with reduced levels of Ikaros consistently mediate better in vitro cell killing and in vivo tumor regression than their wild-type counterparts. This increased anti-tumor activity was accompanied by increased persistence of mesoCAR T cells, as well as increased IFN-γ production. Enhanced cytolytic activity was also evidenced in mesoCAR T cells with reduced Ikaros, which could be partially explained by increased CD107a upregulation and Granzyme B production. Reduction in the Ikaros level in mesoCAR T cells did not affect T cell receptor and CAR signaling, but was able to render them more resistant to soluble inhibitory factors like TGF-β and adenosine. In summary, inhibition of the transcriptional repressor Ikaros in CAR T cells could be an attractive strategy to overcome immunosuppressive tumor microenvironment and enhance their tumoricidal capacity. Further clinical development is warranted.

Citation Format: Shaun O'Brien, Rajan M. Thomas, Steven M. Albelda, Andrew D. Wells, Liang-Chuan S. Wang. Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptor. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B12.
Abstract B14: CD4+CD25+ regulatory T lymphocytes: Prognostic indicator of Chinese breast cancer patients receiving dentitric cells-cytokine induced killer cells infusion
Authors: Song Qing-Kun , Ren Jun , Wang Xiao-Li , Zhou Xin-Na , Yang Hua-Bing , Li Yu-Chen , Wu Jiang-Ping
Published: October 2015

Introduction: Dentitric cell-cytokine induced killer cell infusion is a beneficial immunotherapy for breast cancer among Chinese women. This study aimed to verify the prognostic value of cellular immunity among patients receiving infusions.

Methods: 251 female breast cancer patients participated in the study. Mononuclear cells were harvested from peripheral blood and expanded in vitro. With adequate cell counts, the cultured cells were infused into body. After cell infusion, the cellular immunity was measured by flow cytometry. Progression-free and overall survival were estimated by Kaplan-Meier method with Log-rank test. Cox hazard proportion regression model was used to estimate the hazard ratio and 95% confidence interval.

Results: Proportion of CD4+CD25+ T lymphocyte had a dose-relationship with overall survival (p<0.05), but not progression-free survival. The overall survival was 156 months among patients with lower proportion of CD4+CD25+ T cells compared with 76 months among patients with higher proportion (p<0.05). Higher proportion was associated with a death risk increased by 69% (HR=1.69, 95%CI 1.07, 2.68). Among advanced patients (≥stage III), higher proportion of regulatory T cells were related with hazard ratio of 1.78 (95%CI 1.10, 2.91).

Conclusion: CD4+CD25+ regulatory T lymphocytes were a potential indicator for prognosis of breast cancer patients with the immunotherapy of dentitric cell-cytokine induced killer cells, especially among advanced stage. It might integrated with treatment for further management.

Citation Format: Qing-Kun Song, Jun Ren, Xiao-Li Wang, Xin-Na Zhou, Hua-Bing Yang, Yu-Chen Li, Jiang-Ping Wu. CD4+CD25+ regulatory T lymphocytes: Prognostic indicator of Chinese breast cancer patients receiving dentitric cells-cytokine induced killer cells infusion. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B14.
Abstract B44: The role of CD4 T cells in murine model of NASH-promoted HCC
Authors: Ma Chi , Han Miaojun , Terabe Masaki , Berzofsky Jay , Felsher Dean , Greten Tim
Published: October 2015

Non-alcoholic steatohepatitis (NASH), a common condition in obese patients, is an important risk factor for HCC. However, only little information exists about the immunological mechanisms of how NASH promotes hepatocarcinogenesis. Methionine choline deficient (MCD) diet is widely used to induce NASH. In this study we fed Lap-tTA-myc mice, which develop HCC, with MCD diet. MCD diet accelerated tumor development in MYC on mice. A robust decrease of hepatic CD4 but not CD8 T cells was observed in NASH mice, which was exacerbated by MYC transgene expression. As expected higher level of cell death was detected in these hepatic CD4 T cells. Phenotypic analysis demonstrated that these CD4 T cells had a CD44highCD62Llow effector memory phenotype and produced more IFNγ. Selective CD4 T cell depletion further accelerated HCC development suggesting an important role of these cells for tumor development. Next, we studied the cause of CD4 T cells. In co-culture experiments we demonstrated that lipid-laden hepatocytes from mice on MCD diet induced selective CD4 but not CD8 T cells death through a contact-independent mechanism. FFAs were found from hepatocyte culture medium, and linoleic acid recapitulates the selective toxicity to CD4 T cells. Blocking ROS abolished linoleic acid-induced CD4 T cell death. Our results suggest the critical role of CD4 T cell in the disease progression of NASH to HCC, and provide a new link between lipid metabolism dysfunction with impaired anti-tumor surveillance.

Citation Format: Chi Ma, Miaojun Han, Masaki Terabe, Jay Berzofsky, Dean Felsher, Tim Greten. The role of CD4 T cells in murine model of NASH-promoted HCC. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B44.
Abstract B62: Modulating innate-adaptive immune cell interactions to achieve tumor rejection
Authors: Almeida Ana S. , Kees Tim , Egeblad Mikala
Published: October 2015

A variety of immune cells, the most abundant being macrophages and T cells, typically infiltrate tumors. These immune cells can recognize and kill cancer cells. For example, macrophages activated with interferon-gamma and lipopolysaccharide can kill cancer cells both directly and indirectly, by enhancing the cytotoxic T cells' killing activities. Cancer cells, however, evade the attacking immune cells and even re-instruct macrophages and cytotoxic T cells to facilitate tumor growth, rather than halt it. It is now clear that in a clinical setting T cell deactivation can be overcome using anti-CTLA4 or anti-PDL1 antibodies, leading to tumor regression. Although exciting recoveries are experienced by many patients, the majority of patients do not have long-term benefits of such treatments. Therefore, ways are urgently needed to modify these immune activating approaches so they become beneficial to an expanded patient population.

One underexplored strategy, which we are undertaking, is to re-activate the macrophages so they can kill cancer cells and further enhance the anti-tumor T cell responses. To test different strategies for re-activating macrophages, we are developing co-culture models with cancer cells, T cells and macrophages. In addition, we study interactions between these three cell types in vivo, using intravital imaging of mouse models of breast and pancreatic cancer. Our findings will offer new insights into the mechanisms by immune suppressive signals can be overcome and generate new methods for studying immune responses to cancer in real-time.

Citation Format: Ana S. Almeida, Tim Kees, Mikala Egeblad. Modulating innate-adaptive immune cell interactions to achieve tumor rejection. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B62.
Abstract B88: Combination therapy of reovirus and checkpoint inhibition
Authors: Zaidi Shane , Shim Kevin , Rajani Karishma , Diaz Rosa , Ilett Elizabeth , Kottke Timothy , Thompson Jill , Selby Peter , Harrington Kevin , Pandha Hardev , Melcher Alan , Coffey Matt , Vile Richard
Published: October 2015

We have developed the use of reovirus as a systemically delivered oncolytic agent in both pre-clinical models and in Phase I and II clinical trials. Reovirus has direct oncolytic activity against many human/murine tumor cells, partly because of disruption of the PKR-mediated anti-viral response in malignant cells. In addition however, we have shown that anti-tumor therapy is directly associated with immune activation by virus replication in tumors. The immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, as well as the generation of adaptive anti tumor immune responses as a result of in vivo priming against tumor associated antigens released during that killing. Therefore, to exploit the immune components of reovirus anti-tumor therapy, we tested the combination of oncolytic therapy with systemic checkpoint inhibition. To do this, we used our murine, immune-competent, model and a protocol in which injection of reovirus into subcutaneous (s.c.) B16 melanomas generates moderate therapy following intra-tumoral injection of reovirus into 5d established subcutaneous B16 melanomas growing in C57Bl/6 mice. In this model, provision of systemic anti-PD-1 antibody along with i.t. reovirus, significantly enhanced survival compared to i.t. reovirus alone (p<0.01) and led to >40% of mice being cured long term. Immune analysis suggests that the enhanced therapeutic benefit of reovirus plus checkpoint inhibition is contributed by at least two factors. Thus, blockade of PD-1 significantly enhanced the ability of NK cells to recognize (TNF-α secretion), and kill, reovirus-infected target tumor cells. Second, antiPD-1 antibody led to a significant reduction in Treg activity in reovirus-treated mice, with the overall effect of increasing the adaptive CD8+ anti tumor T cell response. We also showed that timing of the checkpoint inhibitor antibody was significant in balancing toxicity with anti tumor therapy. These data suggest that combination of checkpoint inhibition therapy with reovirus oncolytic/immunotherapy represents a readily translatable method to enhance the therapeutic value of either alone.

Citation Format: Shane Zaidi, Kevin Shim, Karishma Rajani, Rosa Diaz, Elizabeth Ilett, Timothy Kottke, Jill Thompson, Peter Selby, Kevin Harrington, Hardev Pandha, Alan Melcher, Matt Coffey, Richard Vile. Combination therapy of reovirus and checkpoint inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B88.
Abstract IA02: The intersection of inflammation, immunity, and cancer: From basic biology to translational research
Authors: Karin Michael
Published: October 2015

In addition to endogenous genetic alterations, malignant progression and therapeutic responses are strongly modulated by the innate and adaptive immune systems. Androgen depletion and malignant progression induce lymphocyte recruitment into prostate cancer (PC). Recruited B cells produce lymphotoxin (LT), an inflammatory cytokine that stimulates expansion of androgen-deprived PC progenitors. Recruited B cells also control the response of PC to the immunogenic chemotherapeutic agent oxaliplatin, which at a low, non-myelosuppressive dose, induces immunogenic cell death that promotes generation of tumor-directed cytotoxic T cells (CTL). In three different mouse PC models the resulting tumors do not respond to low dose oxaliplatin unless grown in B cell-deficient hosts. The B lymphocytes responsible for immunosuppression are plasma cells that express IgA, IL-10 and PD-L1, but not LT, whose appearance depends on TGFβ-receptor (TGFβR) signaling. Elimination of these cells, which also infiltrate human therapy-resistant PC, facilitates CTL-dependent eradication of oxaliplatin-treated tumors.

References:

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Ammirante, M., Luo, J.L., Grivennikov, S., Nedospasov, S., and Karin, M. (2010). B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464:302-305.

Grivennikov, S.I., Greten, F.R., and Karin, M. (2010). Immunity, inflammation, and cancer. Cell 140:883-899.

Citation Format: Michael Karin. The intersection of inflammation, immunity, and cancer: From basic biology to translational research. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA02.
Abstract IA11: T cell exclusion in pancreatic ductal adenocarcinoma: The FAP+ cancer-associated fibroblast and CXCL12
Authors: Fearon Douglas T. , Pommier Arnaud , Ludwig Michael , Tuveson David
Published: October 2015

Patients with pancreatic adenocarcinoma (PDA), unlike those with melanoma, non-small cell lung cancer and renal cell carcinoma, did not have objective responses to the T cell checkpoint antagonists, antibodies to CTLA-4 and PD-L1, that promote the anti-cancer function of T cells. We sought the basis for this phenomenon by examining the interaction between the immune system and PDA in a genetically engineered mouse model of this disease, the KrasLSL.G12D/+; p53R172H/+; PdxCreTg/+ (or KPC) model. PDA in KPC mice, as in human patients, is resistant to therapy with anti-CTLA-4 and anti-PD-L1, respectively. The explanation for this resistance of the PDA to immune therapy was shown not to be the absence of an anti-cancer cell adaptive immune response, but to be the exclusion of T cells from the vicinity of cancer cells within tumors. The exclusion was caused by the chemokine, CXCL12, that was produced by the carcinoma-associated fibroblasts that were identified by their expression of the membrane protein, FAP. Remarkably, CXCL12 was physically associated with the cancer cells, which were not producing the chemokine. Inhibiting the interaction of this CXCL12 with its receptor, CXCR4, on T cells by administering the drug, AMD3100, caused the rapid accumulation of T cells amongst cancer cells, uncovered the efficacy of anti-PD-L1, and greatly diminished the numbers of cancer cells within the PDA tumors after 6 days of treatment. Thus, pharmacological targeting of the CXCR4-CXCL12 interaction overcomes the dominant immune suppressive mechanism of T cell exclusion in murine PDA. This finding may be relevant to therapy of human PDA, which also exhibits T cell exclusion, coating of cancer cells with CXCL12, and, as noted above, resistance to anti-PD-L1.

Citation Format: Douglas T. Fearon, Arnaud Pommier, Michael Ludwig, David Tuveson. T cell exclusion in pancreatic ductal adenocarcinoma: The FAP+ cancer-associated fibroblast and CXCL12. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA11.
Abstract IA13: Microbiota associations in colon cancer
Authors: Sears Cynthia L.
Published: October 2015

Sporadic colorectal cancer (CRC) results from accumulated DNA mutations in colonic epithelial cells but the factors inducing the causative DNA mutations are unclear. One prime local consideration is the microbiota but little is known about how the microbiota may influence colon carcinogenesis. To further understand the relationship between the microbiota and the colonic epithelium in CRC hosts and non-cancer hosts, we studied the microbiota organization in Carnoy's fixed tissues that preserve the mucus layer of the colonic epithelium and the community composition through microbiome profiling. Unexpectedly, we identified a broad regional change in microbiota organization on colon tissues of the CRC host with invasive polymicrobial bacterial biofilms found commonly on both surgically-resected tumors and normal tissue from the proximal colon. Bacterial biofilms were associated with changes in tissue biology predicted to contribute to colon carcinogenesis. In contrast, the non-tumor host colon epithelial samples did not reveal geographic localization of biofilm formation. High throughput sequencing did not reveal consistent bacterial community membership associated with tumors, regardless of biofilm status. Colon mucosal biofilm detection may contribute to risk for development of sporadic CRC.

Citation Format: Cynthia L. Sears. Microbiota associations in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA13.
Abstract IA22: Regulation of metabolic plasticity in effector T cells
Authors: Jones Russell Graham
Published: October 2015

T lymphocytes are central effectors of the adaptive immune response, and their proper function is critical for long-lasting immunity to foreign pathogens and tumor immunosurveillance. One of the fundamental programs triggered by T cell activation is the reprogramming of cellular metabolism, which is essential to support the bioenergetic and biosynthetic demands of effector T (Teff) cell function. While often considered a “housekeeping” function, cellular metabolism has recently been linked to proper Teff cell differentiation and effector function in vivo, raising the idea that nutrient availability can be immunomodulatory. However, how nutrient availability shapes T cell metabolism and function remains poorly understood. Here we present evidence suggesting that effector T cells possess “metabolic plasticity” and are capable of altering their metabolic programs in response to nutrient availability. We show that T cells possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulates cellular bioenergetics and T cell viability. Effector T cells lacking AMPKα1 display reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we find that AMPKα1 is essential for robust CD4+ and CD8+ T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity. These results and the use AMPK agonists to regulate T cell function will be discussed.

Citation Format: Russell Graham Jones. Regulation of metabolic plasticity in effector T cells. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA22.
Abstract IA24: Vaccines targeting innate immune cells
Authors: Bhardwaj Nina
Published: October 2015

Targeting dendritic cells (DCs) for immunotherapy represents a powerful approach for harnessing the patient's own immune system to eliminate cancer cells or to limit chronic infection. Immunostimulatory DCs as vaccine adjuvants have been applied and tested in both conditions, with some encouraging results. However, immune suppression mediated by tumors and the tumor microenvironment or chronic viral infection, limits the potential of DC based vaccines and compromises DC activity and that of other innate immune cells in the TME. Targeting DC in situ represents another approach to boost immunity in vivo. Along these lines, DC targeted approaches include antibodies that bind DC receptors and agonists or alarmins that prime DC via multiple pattern recognition receptors. The presentation will address the activities of some of these various agents and the imprinting of adjuvant activity upon DC in vitro and in clinical trials. Combining DC targeted vaccines with new approaches that enhance immunogenicity and overcome the regulatory mechanisms underlying peripheral tolerance may be the key to achieving effective and durable immune responses that translate to better clinical outcomes.

Citation Format: Nina Bhardwaj. Vaccines targeting innate immune cells. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA24.
Abstract IA25: Mechanisms of protective tumor immunity
Authors: Dranoff Glenn
Published: October 2015

Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits. We demonstrated that vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF followed by antibody blockade of CTLA-4 accomplishes clinically significant tumor destruction with minimal toxicity in a majority of stage IV metastatic melanoma and some advanced ovarian carcinoma patients. The extent of tumor necrosis in post-treatment biopsies was linearly related to the natural logarithm of the ratio of infiltrating CD8+ effector T cells to FoxP3+ Tregs, suggesting that further Treg inhibition might increase the frequency of clinical responses. Through an analysis of cytokine deficient mice, we delineated a critical role for GM-CSF in Treg homeostasis. GM-CSF is required for the expression of the phosphatidylserine binding protein MFG-E8 in antigen presenting cells, whereas the uptake of apoptotic cells by phagocyte-derived MFG-E8 maintains peripheral Treg activity. The pharmacologic inhibition of MFG-E8 function through genetic or engineering-based approaches blocks Treg induction, which intensifies vaccine-induced responses, leading to the regression of established tumors in mice. The clinical translation of these therapeutic strategies to Phase I testing in humans is underway.

The detailed analysis of patients achieving sustained clinical benefits from irradiated, autologous GM-CSF secreting tumor cell vaccines and CTLA-4 antibody blockade also affords a rich opportunity to identify antigens associated with immune-mediated tumor destruction and to delineate mechanisms of therapeutic immunity. In this regard, we have identified antibodies against a panel of secreted and cell surface proteins that play important roles in tumor development and immune evasion. Isolation of the rare, antigen-specific memory B cells directed towards these important targets provides new opportunities for developing human monoclonal antibodies for cancer immunotherapy.

Citation Format: Glenn Dranoff. Mechanisms of protective tumor immunity. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA25.
Long-Term Toxicity and Quality of Life in Patients Treated for Locally Advanced Cervical Cancer
Authors: Gargiulo Piera , Arenare Laura , Pisano Carmela , Cecere Sabrina Chiara , Falivene Sara , Greggi Stefano , Tambaro Rosa , Facchini Gaetano , De Palma Giampaolo , Scaffa Cono , Della Pepa Chiara , Pignata Sandro , Di Napoli Marilena
Published: October 2015

Objective: The aim of this study was to analyze the long-term toxicity and quality of life (QOL) in patients with locally advanced cervical cancer (LACC) treated with chemoradiation [chemotherapy/radiotherapy (CT/RT)] or neoadjuvant CT (NACT) followed by radical surgery (RS). Methods: Fifty-nine patients with LACC in remission after treatment with NACT + RS (n = 34) or CT/RT (n = 25) were interviewed with an Incontinence Impact Questionnaire (IIQ-7), a Quality of Life Questionnaire (EORTC QLQ-C30), and a Quality of Life Questionnaire for Cervical Cancer (EORTC QLQ-CX24) to compare long-term toxicity and QOL. Results: The mean age was 53 ± 9.8 and 59 ± 11.5 years in the NACT + RS and CT/RT groups, respectively. Overall, diarrhea and constipation were reported in 15 and 68%, respectively, while bladder complaints and a low level of sexual enjoyment were reported in 36 and 47%, respectively. The NACT + RS patients showed a worse sexual activity (74.71 ± 33.57 vs. 92.06 ± 17.96; p = 0.019) and sexual enjoyment (71.21 ± 23.67 vs. 88.88 ± 21.71; p = 0.040) and more frequently complained of constipation (49.01 ± 34.06 vs. 26.66 ± 31.66; p = 0.013), while CT/RT patients more frequently suffered from diarrhea (1.96 ± 7.96 vs. 14.66 ± 28.40; p = 0.017). Conclusions: Many patients treated for LACC have long-term complaints regarding sexual activity and bladder and bowel function. The majority of QOL aspects were similar in the two groups at long-term follow-up. However, diarrhea was more frequent and severe in CT/RT patients, while constipation was more frequent and severe in NACT + RS patients, and they showed a worse sexual life perception. Larger randomized trials addressing these issues are needed.
Um jardim florido? A vegetação cultivada em quintais urbanos através de um gradiente social
Authors: Angeoletto Fabio , Santos Jeater Waldemar Maciel Correa , Ruiz Sanz Juan Pedro
Published: October 2015

Quintais residenciais urbanos possuem um potencial considerável para a conservação da biodiversidade e para a melhoria da qualidade de vida humana. Não obstante, esses espaços não são planificados, e existe pouca informação sobre a diversidade da flora presente nos quintais de moradores de diferentes classes sociais. Quantificamos e comparamos a diversidade vegetal dos quintais de dois bairros da Região Metropolitana de Maringá (RMM), a saber, Jardim das Torres e Zona 02, mediante a identificação das espécies e através do cálculo de índices de diversidade e de correlações bivariadas. Os padrões de diversidade são assaz distintos, quando comparados os bairros, pelo que traçamos diretrizes de planejamento com o objetivo de aumentar a presença de vegetação na RMM, contribuir à conservação da biodiversidade, e, assim, de seus benefícios aos cidadãos.
Endovascular Treatment for Acute Ischemic Stroke in the Setting of Anticoagulation
Authors: Rebello Letícia C. , Haussen Diogo C. , Belagaje Samir , Anderson Aaron , Frankel Michael , Nogueira Raul G.
Published: October 2015

Background and Purpose—

Oral anticoagulation (OAC) plays a major role in atrial fibrillation stroke prevention but represents a contraindication to intravenous tissue-type plasminogen activator. Intra-arterial therapy remains a potential reperfusion strategy in these patients; however, supporting data are scarce.

Methods—

Retrospective analysis of prospectively collected consecutive intra-arterial therapies from October 2010 to March 2015 comparing OAC (vitamin-K antagonists and novel oral anticoagulants) versus normal hemostasis versus intravenous tissue-type plasminogen activator patients. Primary safety end point is parenchymal hematoma. Secondary safety end point is 90-day mortality. Efficacy end points are successful reperfusion (modified Thrombolysis in Cerebral Infarction, 2b-3) and good outcome (90-day modified Rankin Scale score of 0–2). Logistic regression for predictors of parenchymal hematoma was performed.

Results—

A total of 604 patients were qualified for the study. Baseline and outcomes variables were overall similar for vitamin-K antagonists (n=29) and novel oral anticoagulants (n=17) patients. When compared with normal hemostasis (n=265) and intravenous tissue-type plasminogen activator (n=297), OAC (n=46) patients were older and had more comorbidities. There were no statistically significant differences in the rates of parenchymal hematoma (8% versus 5%;
P
=0.42), 90-day modified Rankin Scale score of 0 to 2 (30% versus 40%;
P
=0.26), and 90-day mortality (32% versus 26%;
P
=0.46) among OAC and normal hemostasis patients. Similarly, there were no significant differences between OAC and intravenous tissue-type plasminogen activator patients in terms of parenchymal hematoma (8% versus 4%;
P
=0.16), 90-day modified Rankin Scale score of 0 to 2 (30% versus 43%;
P
=0.13), and 90-day mortality (32% versus 22%;
P
=0.18). The use of OAC was not associated with the occurrence of parenchymal hematoma on multivariate logistic regression analysis.

Conclusions—

Intra-arterial therapy seems to be safe in patients taking OACs; however, our study showed a nonsignificant increase in hemorrhage and mortality with a nonsignificant decrease in good outcomes in comparison with non-OAC patients. Although these nominal differences may have been related to older age and more comorbidities in the OAC group, larger studies are needed to confirm our findings given our limited sample size.
HYDRA2: A Multispectral Data Analysis Toolkit for Sensors on Suomi-NPP and Other Current Satellite Platforms
Authors: Rink Tom , Menzel W. Paul , Gumley Liam , Strabala Kathy
Published: October 2015

The Hyperspectral Data Viewer for Development of Research Applications, version 2 (HYDRA2), is a freeware-based multispectral analysis toolkit for satellite data that assists scientists in research and development, as well as education and training of remote sensing applications. HYDRA2 users can explore and visualize relationships between sensor measurements (brightness temperatures for infrared and reflectances for visible/near-infrared wavelengths) using spectral diagrams, cross sections, scatterplots, multiband combinations, and color enhancements on a pixel-by-pixel basis.

HYDRA2 can be used with direct broadcast and archived data from sensors on board the National Oceanic and Atmospheric Administration (NOAA)/National Aeronautics and Space Administration (NASA) Suomi–National Polar-Orbiting Partnership (Suomi-NPP), NASA Aqua/Terra, European Organisation for the Exploitation of Meteorological Satellites (EUMETSAT) Meteorological Operational (MetOp), and Chinese Fengyun-3 platforms.

This paper describes HYDRA2 and presents some examples using data retrievals from the Suomi-NPP Visible Infrared Imaging Radiometer Suite (VIIRS), Cross-Track Infrared Sounder (CrIS), Advanced Technology Microwave Sounder (ATMS), and Terra/Aqua Moderate Resolution Imaging Spectroradiometer (MODIS) instruments.
Climate Drivers Linked to Changing Seasonality of Alaska Coastal Tundra Vegetation Productivity
Authors: Bieniek Peter A. , Bhatt Uma S. , Walker Donald A. , Raynolds Martha K. , Comiso Josefino C. , Epstein Howard E. , Pinzon Jorge E. , Tucker Compton J. , Thoman Richard L. , Tran Huy , Mölders Nicole , Steele Michael , Zhang Jinlun , Ermold Wendy
Published: October 2015

The mechanisms driving trends and variability of the normalized difference vegetation index (NDVI) for tundra in Alaska along the Beaufort, east Chukchi, and east Bering Seas for 1982–2013 are evaluated in the context of remote sensing, reanalysis, and meteorological station data as well as regional modeling. Over the entire season the tundra vegetation continues to green; however, biweekly NDVI has declined during the early part of the growing season in all of the Alaskan tundra domains. These springtime declines coincide with increased snow depth in spring documented in northern Alaska. The tundra region generally has warmed over the summer but intraseasonal analysis shows a decline in midsummer land surface temperatures. The midsummer cooling is consistent with recent large-scale circulation changes characterized by lower sea level pressures, which favor increased cloud cover. In northern Alaska, the sea-breeze circulation is strengthened with an increase in atmospheric moisture/cloudiness inland when the land surface is warmed in a regional model, suggesting the potential for increased vegetation to feedback onto the atmospheric circulation that could reduce midsummer temperatures. This study shows that both large- and local-scale climate drivers likely play a role in the observed seasonality of NDVI trends.