bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A70: IFN-III is selectively produced by cDC1 and predicts good clinical outcome in human breast cancer
Authors: Hubert Margaux , Couillault Coline , Manh Thien Phong Vu , Ollion Vincent , Lopez-Mestre Helene , Rahmouni Nabil , KIielbassa Janice , Rodriguez Celine , Sajous Christophe , Dumont Benoit , Doffin Anne-Claire , Treilleux Isabelle , Tredan Olivier , Dalod Marc , BendrissS-Vermare Nathalie , Caux Christophe , Valladeau-Guilemomd Jenny
Published: June 2021

Dendritic cells (DCs) play a key role in the orchestration of antitumor immune responses. The cDC1 subset was demonstrated as essential for tumor control and response to immunotherapies in mice, but its precise role in human is largely unexplored. In our study, we combined the analysis of large cohorts of fresh breast and ovarian primary tumors and of public transcriptomic data sets to elucidate human cDC1 functions and clinical impact compared with other DC subsets. We identified a key role for intratumoral cDC1 in producing selectively type III interferon (IFN-III), strongly associated with cytokines and chemokines promoting cytotoxic immune cell recruitment and activation. Of utmost importance, we also revealed a positive impact of IFN-III and cDC1 on patient outcome in many human cancers and identified TLR3-triggering as a therapeutic strategy to trigger IFN-III production by tumor-associated cDC1. These data may pave the way for new IFN or cDC1-targeting antitumor therapies.

Citation Format: Margaux Hubert, Coline Couillault, Thien Phong Vu Manh, Vincent Ollion, Helene Lopez-Mestre, Nabil Rahmouni, Janice KIielbassa, Celine Rodriguez, Christophe Sajous, Benoit Dumont, Anne-Claire Doffin, Isabelle Treilleux, Olivier Tredan, Marc Dalod, Nathalie BendrissS-Vermare, Christophe Caux, Jenny Valladeau-Guilemomd. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in human breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A70.
Abstract A78: IFNg-activated lymphatic vessels express PD-L1 and suppress effector T-cell function in melanoma
Authors: Lane Ryan S. , Breazeale Alec P. , Lund Amanda W.
Published: June 2021

Peripheral tissues adopt mechanisms of immune suppression that counteract protective immunity to prevent immunopathology and are co-opted by tumors for immune escape. In tumors, cytotoxic, antigen-specific T cells produce IFNg and activate multiple mechanisms of adaptive immune resistance, including upregulation of the T-cell inhibitory molecule programed death ligand 1 (PD-L1). Tumor cell PD-L1 expression does not predict response to anti-PD-L1 immunotherapy, indicating, however, that other sources of PD-L1 in tumor microenvironments may contribute to PD-L1-dependent immune suppression. Lymphatic vessels facilitate antigen and dendritic cell transport to draining lymph nodes and are required for antitumor immunity. Interestingly, lymphatic endothelial cells in lymph nodes are tolerogenic at steady-state and constitutively express PD-L1 to delete self-reactive CD8+ T cells. However, whether lymphatic endothelial cells in tumor microenvironments are also directly immunosuppressive remains unclear. Here we test the hypothesis that peripheral, tumor-associated lymphatic vessels acquire immunosuppressive mechanisms, e.g., PD-L1 expression, that limit effector CD8+ T-cell accumulation and function in melanoma. We demonstrate that host nonhematopoietic, nontumor, PD-L1 limits CD8+ T-cell accumulation in murine melanoma. Further, we show that tumor-associated lymphatic endothelial cells upregulate PD-L1 in response to IFNg produced by tumor-infiltrating, antigen-specific CD8+ T cells. As such, loss of IFNgR by lymphatic endothelial cells improves CD8+ T-cell accumulation in murine melanomas, thereby enhancing tumor control and improved overall survival. Importantly, this robust lymphatic vessel-dependent tumor control was revealed in the context of murine melanomas with significant UVB-induced somatic mutation burden, consistent with a cytotoxic T cell-mediated negative feedback mechanism. Consequently, we present IFNg-mediated activation of tumor-associated lymphatic vessels as a new component of adaptive immune resistance, suggesting that context-dependent lymphatic vessel function may provide novel, targetable mechanisms of immune control in melanoma.

Citation Format: Ryan S. Lane, Alec P. Breazeale, Amanda W. Lund. IFNg-activated lymphatic vessels express PD-L1 and suppress effector T-cell function in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A78.
Abstract A87: Acetaminophen pretreatment stimulated interferon γ-induced PD-L1 protein expression in vitro and CD68 positive macrophage infiltration in tumor xenograft
Authors: Wu Jeffrey , Neuwelt Alexander J. , Muldoon Leslie L. , Neuwelt Edward A.
Published: June 2021

Immunotherapy targeting the programmed cell death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) pathway using antibodies is clinically effective in treating a spectrum of cancers. Acetaminophen (AAP) has shown antitumor and/or chemo-enhancing effects in human cancer cells in vitro and in vivo. We investigated the effects of AAP exposure on cancer cells’ immune checkpoint PD-L1 expression in vitro and their in vivo tumorigenic ability. Acetaminophen (10 mM) alone for 2 hr has no effect on cell viability and no effect on PD-L1 level of A2058 melanoma and H460 non-small cell lung carcinoma in vitro. However, AAP treatment for 2 hr followed by interferon-γ (20 ng/ml) stimulated PD-L1 protein expression. The stimulatory effect of AAP pretreatment was not replicated with other glutathione-depleting reagents, including hydrogen peroxide (100 μM; 2hr) or buthionine sulfoximine (50 μM; 24hr). For the in vivo tumorigenesis study, cancer cells (2.5x107) pretreated with AAP developed significantly (p=0.0028 in A2058 and p=0.002 in H460) smaller tumor size after being subcutaneously implanted into athymic rats. Compared to vehicle control, AAP also showed more tumor CD68+ macrophage infiltration by immunohistochemistry. Our results demonstrate for the first time the short-time exposure of AAP inhibited tumor growth by enhancing CD68+ macrophage infiltration. We conclude that high-dose AAP may be immune modulatory, a cell marker regulator and it could be potentially used as a single agent or in combination with other immunotherapy drugs to facilitate therapeutic efficacy.

Citation Format: Jeffrey Wu, Alexander J. Neuwelt, Leslie L. Muldoon, Edward A. Neuwelt. Acetaminophen pretreatment stimulated interferon γ-induced PD-L1 protein expression in vitro and CD68 positive macrophage infiltration in tumor xenograft [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A87.
Abstract B02: Ephrin receptor A10 promotes PD-L1 expression for breast cancer immune evasion
Authors: Chan Li-Chuan , Cha Jong-Ho , Yang Wen-Hao , Xia Weiya , Lee Heng-Huan , Wang Ying-Nai , Hsu Jennifer L. , Ren Guoxin , Hung Mien-Chie
Published: June 2021

Programmed death-ligand 1(PD-L1) is an immune checkpoint protein and its engagement with programmed cell death protein-1 (PD-1) receptor on T cells activates co-inhibitory signaling to induce cancer immune evasion. PD-L1 or PD-1 blockade has demonstrated encouraging clinical outcomes in several advanced cancer treatment. Elucidating the regulatory mechanisms of PD-L1 is critical to improve the efficiency of PD-L1-targeting immunotherapy. Recent studies indicated that contact-dependent pathways downregulate anticancer immunity, highlighting the importance of cell contact-induced signaling for cancer immune escape. In this study, we show that tumor cell contact promotes PD-L1 expression and reduces immune surveillance via membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is only expressed in normal testis tissue and mediates cell contact-dependent juxtacrine signaling. Abolishing the expression of EphA10 enhances T-cell-mediated antitumor immunity in 4T1 mouse model. A positive correlation between EphA10 and PD-L1 expression is observed in human breast cancer tissues. Overall, our findings indicate that cell contact-mediated juxtacrine signaling increases PD-L1 expression, suggesting that tumor cells avoid immune surveillance via this mechanism and blockade of EphA10 may be a new immunotherapy strategy for breast cancer patients.

Citation Format: Li-Chuan Chan, Jong-Ho Cha, Wen-Hao Yang, Weiya Xia, Heng-Huan Lee, Ying-Nai Wang, Jennifer L. Hsu, Guoxin Ren, Mien-Chie Hung. Ephrin receptor A10 promotes PD-L1 expression for breast cancer immune evasion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B02.
Abstract B07: Oncolytic adenovirus 3 coding for CD40L as an enhancer of dendritic cell therapy
Authors: Santos João Manuel , Hemminki Akseli , Siurala Mikko , Hemminki Otto , Havunen Riikka , Cervera-Carrascon Victor , Sorsa Suvi , Wang Hongjie , Lieber Andre , de Gruijl Tanja , Kanerva Anna , Zafar Sadia
Published: June 2021

Dendritic cell (DC) therapy is considered a promising immunotherapeutic approach for treatment of advanced cancer. However, the immunosuppressive tumor microenvironment leads to DC dysfunction. Therefore, in clinical trials DC therapy has generally failed to fulfill its expectations. Oncolytic adenoviruses are well tolerated and have shown to activate antitumor immune responses. Importantly, they can convert immunosuppression locally into a proinflammatory state. To improve the proper activation of transferred DCs, we armed oncolytic adenovirus with CD40 ligand (CD40L). CD40L is known to play an important role in the regulation of immune cells through its capacity to stimulate dendritic cells that leads to the activation of cytotoxic T cells. Therefore, we generated a novel virus Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 adenovirus (Ad3) for intravenous delivery. It features a human telomerase reverse transcriptase (hTERT) promoter for tumor specific replication and expresses human CD40L (hCD40L) under a cytomegalovirus (CMV) promoter for induction of antitumor efficacy. Of note, human and animal data have shown the ability of Ad3 to successfully reach tumors through the intravenous route. In syngeneic studies in an immunocompetent model, DC therapy with our murine CD40L-armed adenovirus showed significant antitumor immune response. This enhanced therapeutic effect is associated with increased tumor specific T cells and induction of T-helper type 1 immune response. This synergistic effect was further evaluated in mice humanized with human peripheral blood mononuclear cells. Treatment with hCD40L-armed adenovirus and human DCs showed 100% survival in conjunction with tumor control. To conclude, CD40L armed oncolytic adenovirus 3 improves DC therapy by favorable alteration of tumor microenvironment. These findings support clinical trials where DC therapy is enhanced with oncolytic adenovirus.

Citation Format: João Manuel Santos, Akseli Hemminki, Mikko Siurala, Otto Hemminki, Riikka Havunen, Victor Cervera-Carrascon, Suvi Sorsa, Hongjie Wang, Andre Lieber, Tanja de Gruijl, Anna Kanerva, Sadia Zafar. Oncolytic adenovirus 3 coding for CD40L as an enhancer of dendritic cell therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B07.
Abstract B11: RAS orchestrates the increase of interstitial adenosine in lung adenocarcinoma to promote immune evasion
Authors: de Carné Sophie , East Philip , Moore Chris , Downward Julian
Published: June 2021

The RAS pathway is frequently activated in human cancers, including lung adenocarcinoma, leading to poor prognosis and resistance to therapy. Despite huge efforts, it is still not possible to target this pathway directly. In contrast, Immune checkpoint blockade has shown remarkable yet varied efficacy in lung cancer. With the aim of finding a vulnerable point in these aggressive tumors, we ask here whether oncogenic RAS shapes the immune landscape of lung adenocarcinoma. We classified human lung adenocarcinoma (LUAD) samples from the publicly available dataset from TCGA according to their RAS activity using a RAS transcriptional signature. We correlated the fraction of twenty-two types of leucocyte present in the samples with RAS activity using CIBERSORT. We also identified the expression of immune-related genes that were associated with RAS activity. We observed that RAS activity correlated with the recruitment of proinflammatory macrophages and neutrophils. RAS activity also correlated with the expression of several immune checkpoint genes (e.g., CD274 (PD-L1), HAVCR2 (TIM-3)) as well as genes related to adenosine metabolism or function (e.g., NT5E (CD73), SLC29A4 (ENT4)). Interstitial adenosine is known to dampen the antitumoral immune response. We validated that NT5E expression was dependent on the RAS-MAPK pathway in vitro in human lung cancer cell lines and in vivo in the KrasG12D-LSL/wt Trp53fl/fl mouse model of lung adenocarcinoma. RAS-active tumors could evade the immune system by increasing adenosine level in the tumor microenvironment, notably by increasing expression of CD73, the enzyme that converts extracellular AMP to adenosine. Patients with highly aggressive and resistant RAS-driven lung cancers could benefit from targeting adenosine metabolism (anti-CD73) or activity (A2AR inhibitors) in combination with other immunotherapies targeting PD-1/PD-L1 and TIM-3.

Citation Format: Sophie de Carné, Philip East, Chris Moore, Julian Downward. RAS orchestrates the increase of interstitial adenosine in lung adenocarcinoma to promote immune evasion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B11.
Abstract B12: Quantitative high-resolution tissue analysis defines intratumoral hot spots of PMN-MDSC activity in situ
Authors: Si Yu , Squire Anthony , Merz Simon , Bruderek Kirsten , Lang Stephan , Gunzer Matthias , Brandau Sven
Published: June 2021

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of myeloid cells with T-cell suppressive activity. While the identity and function of circulating MDSC is fairly well established in human cancer patients, the nature of potential MDSC in tissues remains largely enigmatic. However, understanding the biology of MDSC in human tissues is of pivotal importance, because MDSC are believed to regulate the activity of antitumor T cells and may serve as a major resistance mechanism in modern cancer immunotherapy. We developed a whole-mount tissue processing and staining procedure to mark PMN-MDSC subsets and T-cell effector function in situ in an intact 3-dimensional tissue architecture. We then used ultramicroscopy, digital image analysis and 3-D image reconstruction of original data to analyze and quantify the spatial distribution of MDSC and T cells. We identified intratumoral hot spots with high prevalence for both MDSC and T cells. T-cell effector function was reduced in these hot spots. Multicolor immunofluorescence and high-resolution image analysis also revealed the identity and frequency of cellular conjugates between MDSC and T cells. Quantitative spatial analyses indicated that immunosuppressive activity of MDSC requires close proximity of MDSC and T cells. Obtained data were applied to 2-D multicolor immunofluorescence analysis in a larger cohort of head and neck cancer patients with well-defined follow-up. Patients with evidence for strong downregulation of T-cell activity by PMN-MDSC presented with a significantly impaired survival, suggesting a clinical relevance of our findings. Our data suggest that co-targeting of PMN-MDSC and T cells could be beneficial in a subgroup of cancer patients. We also identified parameters useful to select those patients, who are likely to benefit from such immuno-combinations.

Citation Format: Yu Si, Anthony Squire, Simon Merz, Kirsten Bruderek, Stephan Lang, Matthias Gunzer, Sven Brandau. Quantitative high-resolution tissue analysis defines intratumoral hot spots of PMN-MDSC activity in situ [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B12.
Abstract B17: Exosomal PD-L1 harbors active defense function to suppress T-cell activity and promote breast cancer tumor growth
Authors: Yang Yi , Li Chia-Wei , Chan Li-Chuan , Wei Yongkun , Hsu Jung-Mao , Xia Weiya , Cha Jong-Ho , Hou Junwei , Hsu Jennifer L. , Sun Linlin , Hung Mien-Chie
Published: June 2021

Tumor cell-derived exosomes play important roles in tumor-microenvironment regulations, and PD-L1 plays a passive protective role in the tumor microenvironment for tumor growth and progression. Our research revealed that PD-L1 exists in exosomes derived from human and mouse breast cancer cells and can be transferred to other cancer cells, rendering PD-L1-negative cancer cells PD-L1 positive and escape from T-cell killing. By binding to its receptor PD-1 to inhibit T-cell antitumor function, exosomal PD-L1 from cancer cells harbors active defense function to protect and promote tumor growth of breast cancer cells. Together with both genetic approach and pharmacologic inhibitor, the results suggested that blockage of exosome-PD-L1 secretion likely contribute significantly to antitumor immunity, and the combined inhibition of exosome secretion and anti-PD-L1 therapy has the potential to improve antitumor response in the clinic.

Citation Format: Yi Yang, Chia-Wei Li, Li-Chuan Chan, Yongkun Wei, Jung-Mao Hsu, Weiya Xia, Jong-Ho Cha, Junwei Hou, Jennifer L. Hsu, Linlin Sun, Mien-Chie Hung. Exosomal PD-L1 harbors active defense function to suppress T-cell activity and promote breast cancer tumor growth [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B17.
Abstract B96: Pharmacodynamic studies of SB 11285, a systemically bioavailable STING agonist in orthotopic tumor models
Authors: Challa Sreerupa , Ramachandran Balaji , Vijayakrishnan Lalitha , Weitzel Douglas , Zhou Shenghua , Iyer Kris
Published: June 2021

Background: The activation of innate and adaptive immunity via Stimulator of Interferon Genes (STING) signaling is a potentially transformative immunotherapeutic strategy in cancer. We have previously reported that SB 11285 is a novel and highly potent STING agonist that can be delivered by intravenous, intraperitoneal and intratumoral routes. We report here the antitumor and pharmacodynamic studies of SB 11285 in multiple orthotopic and subcutaneous syngeneic mouse tumor models.

Methods: (1) Orthotopic NBT-II syngeneic rat bladder model: Rat bladder tumor cells were surgically implanted in the bladder wall of rats (n =10). After 6 days, SB 11285 was administered by i.v. @ 0.5, 1.5, and 3mg/kg on days 1, 5, 9,1 3, 17, 21, 25 and 31. Groups of rats treated with docetaxel at 7.5mg/kg i.v. and saline were used as positive and negative controls, respectively. At the end of dosing period, the bladders were harvested and evaluated by measurement of bladder weight and gross pathology. (2) Pharmacodynamic (PD) studies: Syngeneic mouse subcutaneous CT26 colon carcinoma and orthotopic 4T1 breast cancer models were used. In the CT26 model, when mean tumor volume (MTV) reached 125mm3, SB 11285 was administered at 3mg/kg i.v on days 1 and 5. In the orthotopic 4T1 model, SB 11285 was administered i.p. @ 10mg/kg on days 5, 7, 9, 11, 13, 17 and 19. Blood, lymph nodes, spleen and tumor were harvested and evaluated for (i) cytokine analysis by multiplexing assays and (ii) enumeration of CD4+, CD8+, Tregs, macrophages and MDSCs in blood, lymph nodes, spleen and tumor.

Results: (1) In the orthotopic NBT-II rat bladder study, animals that received SB 11285 in all doses remained tumor-free based upon gross pathology and bladder weight measurements. SB 11285 was shown to be well tolerated and safe. (2) In both the 4T1 and CT26 PD studies, cytokine analysis of blood and tissues showed strong induction of type I interferon signature without significant systemic inflammatory response. Flow cytometric analysis of blood, lymph nodes, spleen and tumor revealed significant increase in macrophage & CD8+ T-cell infiltration and decrease in Tregs & CD4+ T-cell infiltration.

Conclusion: SB 11285 showed potent antitumoral activity in multiple orthotopic and subcutaneous models that correlated with antitumoral immune response mediated by the induction of IFNs, and ISGs and other cytokines along with reduction of Tregs. SB 11285 is being advanced to human clinical trials.

Citation Format: Sreerupa Challa, Balaji Ramachandran, Lalitha Vijayakrishnan, Douglas Weitzel, Shenghua Zhou, Kris Iyer. Pharmacodynamic studies of SB 11285, a systemically bioavailable STING agonist in orthotopic tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B96.
Abstract IA06: Tumor and host factors regulating antitumor immunity and immunotherapy efficacy
Authors: Gajewski Thomas F.
Published: June 2021

Two major phenotypes of human melanoma metastases have been observed based on gene expression profiling and confirmatory assays. One subgroup of patients has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and appears to display immune “exclusion.” The mechanisms of immune escape are likely distinct in these two subsets, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs. Deep analysis of tumor antigen-specific T cells in the tumor microenvironment has identified additional mechanisms of immune dysfunction and new potential therapeutic targets. Treatment strategies targeting several pathways have been translated back into the clinic, with anti-PD-1/PD-L1 agents being FDA approved for 11 different cancer entities. Combinations with new agents based on the biology of T-cell dysfunction are ongoing. In contrast to the T cell-inflamed melanomas, non-T cell-inflamed tumors are largely immunotherapy resistant with current approaches. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8+ DCs, and these factors are absent in non-T cell-inflamed tumors. New strategies are being developed to engage or mimic this pathway as a therapeutic endeavor, including STING agonists. The molecular mechanisms that mediate the absence of the T cell-inflamed tumor microenvironment in patients are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway, which argues that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment. Recent evidence has indicated that host factors, including the intestinal microbiota, are also critical. We recently have identified commensal bacteria in mouse models that augment spontaneous antitumor immunity and increase efficacy of anti-PD-L1 therapy. Similar analyses in human melanoma patients revealed commensal bacteria associated with anti-PD-1 efficacy. These results have prompted the pursuit of new probiotics that may improve spontaneous immune infiltration and expand immunotherapy efficacy in the clinic.

Citation Format: Thomas F. Gajewski. Tumor and host factors regulating antitumor immunity and immunotherapy efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA06.
Abstract IA20: Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures
Authors: Allison James P.
Published: June 2021

The existence of multiple nonredundant inhibitory pathways that limit T-cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T-cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen-presenting cells. Antibodies to CTLA-4 have proved effective against multiple tumor types in both preclinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long-term (>4 years) survival benefit in about 20% of patients in a randomized, placebo-controlled trial in late-stage melanoma. In 2011 it was approved by the FDA for treatment of late-stage melanoma, and it remains part of the standard of care for that disease. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T-cell antigen receptor-mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25%. Combination of anti-PD-1 and anti-CTLA-4 in melanoma provides objective responses in about 50% of late-stage melanoma patients. The FDA has now approved 6 different checkpoint antibodies for a variety of cancers including urothelial, renal, and lung cancers. A major focus of current efforts is the rational identification of combinatorial treatments that improve the response rate and expand the range of immune checkpoint inhibitors. We used high-parameter flow cytometry to identify the mostly nonoverlapping cellular mechanisms of CTLA-4 and PD-1 blockade, which may partially explain the enhanced effect of their combination. Further work has shown that combined CTLA-4 and PD-1 blockade, which provides higher response rates against a wider range of cancers than either monotherapy, acts through a population of T cells not enriched in either single treatment. T-cell responses are largely directed toward neoantigens arising as a result of mutational events associated with the carcinogenesis. While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, tumors with lower burdens of mutations (e.g., prostate, breast, and kidney cancer) present special challenges for immune therapy. Recent evidence suggests that even the few neoantigens carried by these can provide targets for immune attack. Strategies for effective treatment of such tumors will be discussed.

Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA20.
Abstract PR18: A novel immunomodulatory strategy of targeting glyco-immune checkpoints using EAGLE technology to treat cancer
Authors: Peng Li , Petrone Adam , Cao Lizhi , Broderick James
Published: June 2021

Cancer therapy has been revolutionized by inhibiting immune checkpoints to harness the power of the immune system in fighting cancer. However, the majority of patients are resistant to the current immuno-oncology drugs. There is a strong need to identify novel mechanisms of immune evasion in cancer and explore novel therapeutic modalities. Recently, glyco-immune checkpoints have been identified as an important modulator in cancer immune escape. Upon ligation of cancer-specific sialylated glycans, glyco-immune checkpoints suppress multiple facets of cancer immunity, including cancer antigen release, cancer antigen presentation, and priming and activation anticancer T-cell immunity. However, due to the complexity and heterogeneity of cancer sialylated glycans and the profound species differences of the glyco-immune checkpoints between human and mouse, this immunomodulatory pathway remains unexplored for therapeutic interventions. Here we described a novel multifunctional antibody-like therapeutic modality, named EAGLE (Enzyme-Antibody Glyco-Ligand Editing), to target this glyco-immune checkpoint axis. EAGLE overcomes the complexity of cancer glycans and specifically cleaves the immunosuppression-mediating key sugar moieties, the terminal sialic acids of various sialylated glycans on tumor cells. We hypothesized that EAGLE could block the immunosuppressive glyco-immune checkpoints in the tumor microenvironment and potentiate innate and adaptive immune responses to treat cancer. Indeed, systematic delivery of an EAGLE molecule decreased the levels of immunosuppressive sialic acids on tumor cells, and increased T-cell infiltration and activation in syngeneic tumor models. EAGLE treatment led to 50% complete regressions of established tumors as a monotherapy, and 100% cures in combination with anti-PD1 mAb. Furthermore, cured mice from EAGLE treatment completely rejected the rechallenge of tumor cells, suggesting that EAGLE induced antitumor immunologic memory. In summary, we demonstrated that this novel therapeutic modality, EAGLE, can release glyco-immune checkpoint-mediated immunosuppression in the tumor microenvironment and potentiate innate and adaptive antitumor immunity, which offers a novel and promising immunomodulatory strategy to treat cancer.

This abstract is also being presented as Poster A91.

Citation Format: Li Peng, Adam Petrone, Lizhi Cao, James Broderick. A novel immunomodulatory strategy of targeting glyco-immune checkpoints using EAGLE technology to treat cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR18.
Abstract PR21: IL-35+ B cells establish immunosuppressive network in pancreatic ductal adenocarcinoma
Authors: Mirlekar Bhalchandra , Pylayeva-Gupta Yuliya
Published: June 2021

Despite advances in our understanding of the mutational landscape in pancreatic ductal adenocarcinoma (PDAC), this devastating disease is now the third-leading cause of U.S. cancer-related deaths. While recent successes of cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic cancer. A major barrier for immunotherapeutic approaches is marked immunosuppression within the PDAC milieu. We have previously identified a novel role for IL-35-producing B cells in the pathogenesis of pancreatic cancer. However, little is known about the mechanisms behind IL-35 activity in cancer. Here, we set out to elucidate molecular and cellular mechanisms by which IL-35 facilitates the emergence of pancreatic cancer. Our results demonstrate that IL-35, but not IL-10, potentiates PDAC growth. This correlates with induction of regulatory T cells and suppression of effector T-cell activity, suggesting that IL-35 controls endogenous antitumor immune responses in PDAC. Furthermore, while IL-35 is expressed by several immune cell types in PDAC, we show that its expression specifically in B cells is essential for suppression of antitumor T-cell responses. Importantly, while PDAC is typically resistant to anti-PD-1 immunotherapy, we demonstrate robust synergistic reduction in tumor growth when IL-35 deficiency is combined with anti-PD-1 treatment. Insights gleaned from these and further mechanistic studies of IL-35 in PDAC may be expeditiously translated into IL-35 targeted combination immunotherapy.

This abstract is also being presented as Poster A28.

Citation Format: Bhalchandra Mirlekar, Yuliya Pylayeva-Gupta. IL-35+ B cells establish immunosuppressive network in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR21.
First Report of a de novo 10q23.31q23.33 Microdeletion: Obesity, Intellectual Disability and Microcephaly
Authors: Turkyilmaz Ayberk , Kurnaz Erdal , Cayir Atilla
Published: June 2021

Intellectual disability (ID) is characterized by limited or insufficient development of mental abilities, including intellectual functioning impairments, such as learning and understanding cause-effect relationships. Some cases have ID as the only finding and are called isolated cases. Conversely, cases accompanied by facial dysmorphism, microcephaly, autism spectrum disorder, epilepsy, obesity, and congenital anomalies are called syndromic developmental delay (DD)/ID. Isolated and syndromic DD/ID cases show extreme genetic heterogeneity. Genetic etiology can be detected in approximately 40% of the cases, whereas chromosomal abnormalities are observed in 25%. Obesity is a multifactorial disease in which both genetic and environmental factors play important roles. The role of heredity in obesity has been reported to be between 40 and 70%. Array-based comparative genomic hybridization (array-CGH) can detect CNVs in the whole genome at a higher resolution than conventional cytogenetic methods. Array-CGH is currently recommended as the first-tier genetic test for ID cases worldwide. In the present study, we aimed to evaluate clinical, radiological, and genetic analyses of a 12-year and 4-month-old girl with microcephaly, ID, and obesity. In the array-CGH analysis, a 3.1-Mb deletion, arr[GRGh37] 10q23.31g23.33 (92745793_95937944)×1 was detected, and this alteration was evaluated to be pathogenic. We consider that haploinsufficiency of the candidate genes (GPR120, KIF11, EXOC6, CYP26A1, CYP26C1, and LGI1) in the deletion region may explain microcephaly, ID, obesity, seizures, and ophthalmological findings in our patient. The investigation of 10q23.31q23.33 microdeletion in cases with syndromic obesity may contribute to molecular genetic diagnosis.
Temperature-Induced Sex Reversal in Reptiles: Prevalence, Discovery, and Evolutionary Implications
Authors: Whiteley Sarah L. , Castelli Meghan A. , Dissanayake Duminda S.B. , Holleley Clare E. , Georges Arthur
Published: June 2021

Sex reversal is the process by which an individual develops a phenotypic sex that is discordant with its chromosomal or genotypic sex. It occurs in many lineages of ectothermic vertebrates, such as fish, amphibians, and at least one agamid and one scincid reptile species. Sex reversal is usually triggered by an environmental cue that alters the genetically determined process of sexual differentiation, but it can also be caused by exposure to exogenous chemicals, hormones, or pollutants. Despite the occurrence of both temperature-dependent sex determination (TSD) and genetic sex determination (GSD) broadly among reptiles, only 2 species of squamates have thus far been demonstrated to possess sex reversal in nature (GSD with overriding thermal influence). The lack of species with unambiguously identified sex reversal is not necessarily a reflection of a low incidence of this trait among reptiles. Indeed, sex reversal may be relatively common in reptiles, but little is known of its prevalence, the mechanisms by which it occurs, or the consequences of sex reversal for species in the wild under a changing climate. In this review, we present a roadmap to the discovery of sex reversal in reptiles, outlining the various techniques that allow new occurrences of sex reversal to be identified, the molecular mechanisms that may be involved in sex reversal and how to identify them, and approaches for assessing the impacts of sex reversal in wild populations. We discuss the evolutionary implications of sex reversal and use the central bearded dragon (Pogona vitticeps) and the eastern three-lined skink (Bassiana duperreyi) as examples of how species with opposing patterns of sex reversal may be impacted differently by our rapidly changing climate. Ultimately, this review serves to highlight the importance of understanding sex reversal both in the laboratory and in wild populations and proposes practical solutions to foster future research.
Cerebral Vasculitis in a COVID-19 Confirmed Postpartum Patient: A Case Report
Authors: Chua Audrey Marie U. , Jamora Roland Dominic G. , Jose Arianne Crizielle E. , Anlacan Veeda Michelle M.
Published: June 2021

COVID-19 has primarily been reported as a respiratory illness, but involvement of other organ systems has been reported. We describe a case of a postpartum with COVID-19 who had cerebral vasculitis. The patient presented with headache, blurring of vision, right-sided body weakness, and incoordination. Cranial magnetic resonance imaging (MRI) and angiography (MRA) showed a small acute hemorrhage on the left occipital lobe with associated acute subarachnoid hemorrhage along the parietal and occipital convexities and bilateral moderate to severe narrowing of the cerebral vessels. The patient was discharged asymptomatic. On follow-up, patient had no residual neurologic deficits, and repeat cranial MRI/MRA showed complete resolution of the vasculitis. This report was compatible with the pattern of viral-induced vasculitis and provides support to the mechanism of COVID-19-associated neurologic manifestation.
Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region
Authors: Shemesh Colby S. , Chan Phyllis , Shao Hui , Xu Derek-Zhen , Combs Daniel , Vadhavkar Shweta , Bruno René , Wu Benjamin
Published: June 2021

Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.
Transdiagnostic versus Diagnosis-Specific Group Cognitive Behavioral Therapy for Anxiety Disorders and Depression: A Randomized Controlled Trial
Authors: Reinholt Nina , Hvenegaard Morten , Christensen Anne Bryde , Eskildsen Anita , Hjorthøj Carsten , Poulsen Stig , Arendt Mikkel Berg , Rosenberg Nicole Kristjansen , Gryesten Jasmin Rejaye , Aharoni Ruth Nielsen , Alrø Anja Johnsen , Christensen Clas Winding , Arnfred Sidse Marie
Published: June 2021

Introduction: The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) delivered in a group format could facilitate the implementation of evidence-based psychological treatments. Objective: This study compared the efficacy of group UP and diagnosis-specific cognitive behavioral therapy (dCBT) for anxiety and depression in outpatient mental health services. Methods: In this pragmatic, multi-center, single-blinded, non-inferiority, randomized controlled trial (RCT), we assigned 291 patients with major depressive disorder, social anxiety disorder, panic disorder, or agoraphobia to 14 weekly sessions in mixed-diagnosis UP or single-diagnosis dCBT groups. The primary test was non-inferiority, using a priori criteria, on the World Health Organisation 5 Well-Being Index (WHO-5) at the end of the treatment. Secondary outcomes were functioning and symptoms. We assessed outcomes at baseline, end-of-treatment, and at a 6-month follow-up. A modified per-protocol analysis was performed. Results: At end-of-treatment, WHO-5 mean scores for patients in UP (n = 148) were non-inferior to those of patients in dCBT (n = 143; mean difference –2.94; 95% CI –8.10 to 2.21). Results were inconclusive for the WHO-5 at the 6-month follow-up. Results for secondary outcomes were non-inferior at end-of-treatment and the 6-month follow-up. Client satisfaction and rates of attrition, response, remission, and deterioration were similar across conditions. Conclusions: This RCT demonstrated non-inferior acute-phase outcomes of group-delivered UP compared with dCBT for major depressive disorder, social anxiety disorder, panic disorder, and agoraphobia in outpatient mental health services. The long-term effects of UP on well-being need further investigation. If study findings are replicated, UP should be considered a viable alternative to dCBT for common anxiety disorders and depression in outpatient mental health services.
Ruxolitinib for Severe COVID-19-Related Hyperinflammation in Nonresponders to Steroids
Authors: Sarmiento Mauricio , Rojas Patricio , Jerez Joaquin , Bertín Pablo , Campbell James , García Maria J. , Pereira Jaime , Triantafilo Nicolas , Ocqueteau Mauricio
Published: June 2021

Introduction: Currently, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is a major public health problem worldwide. Although most patients present a mild infection, effective strategies are required for patients who develop the severe disease. Anti-inflammatory treatment with JAK inhibitors has been considered in SARS-CoV-2. Methods: In this study, we presented our experience in a group of severe SARS-CoV-2 Chilean patients. This prospective study was performed on consecutive patients presenting severe respiratory failure owing to COVID-19 or high-risk clinical condition associated with SARS-CoV-2, and who were treated with ruxolitinib for management of associated inflammation. Overall, 18 patients presenting SARS-CoV-2 viral-induced hyperinflammation were treated with ruxolitinib, with 16 patients previously treated with steroids, 4 with tocilizumab, and 3 with both treatments. Results: Ten patients evolved with favorable response, including 7 patients admitted with severe respiratory failure (PaFi less than 200 mm Hg in high-flow nasal cannula), presenting complete regression of hyperinflammation, regression of the lung lesions, and subsequent discharge. In the remaining 8 patients, 25% showed reduced inflammation, but early discharge was not achieved owing to the slow evolution of respiratory failure. Unfortunately, 3 patients demonstrated a severe respiratory failure. The early initiation of ruxolitinib was found to be associated with better clinical evolution (p < 0.005). Conclusion: In this study, ruxolitinib resolved hyperinflammatory state in 55% of the patients, regardless of the previous steroid or tocilizumab therapy. Unfortunately, few patients demonstrated severe evolution despite ruxolitinib therapy. Notably, the treatment starting time appears to play an important role in achieving good outcomes. Further validation in randomized controlled trials is crucial.
A Novel Model of Fetal Spinal Cord Exposure Allowing for Long-Term Postnatal Survival
Authors: Stokes Sarah C. , Jackson Jordan E. , Theodorou Christina M. , Pivetti Christopher D. , Kumar Priyadarsini , Yamashiro Kaeli J. , Wang Aijun , Farmer Diana L.
Published: June 2021

Background: The inherent morbidity associated with fetal ovine models of myelomeningocele (MMC) has created challenges for long-term survival of lambs. We aimed to develop a fetal ovine surgical spinal exposure model which could be used to evaluate long-term safety after direct spinal cord application of novel therapeutics for augmentation of in utero MMC repair. Methods: At gestational age (GA) 100–106, fetal lambs underwent surgical intervention. Laminectomy of L5–L6 was performed, dura was removed, and an experimental product was directly applied to the spinal cord. Paraspinal muscles and skin were closed and the fetus was returned to the uterus. Lambs were delivered via cesarean section at GA 140–142. Lambs were survived for 3 months with regular evaluation of motor function by the sheep locomotor rating scale. Spinal angulation was evaluated by magnetic resonance imaging at 2 weeks and 3 months. Results: Five fetal surgical intervention lambs and 6 control lambs who did not undergo surgical intervention were included. All lambs survived to the study endpoint of 3 months. No lambs had motor function abnormalities or increased spinal angulation. Conclusion: This model allows for long-term survival after fetal spinal cord exposure with product application directly onto the spinal cord.
A Challenging Case of a Physeal Bar Endoscopic-Assisted Resection in a Short Stature Child: Case Report and Literature Review
Authors: Ribau Melanie , Baptista Mário , Oliveira Nuno , Direito Santos Bruno , Varanda Pedro , Maia Ricardo
Published: June 2021

Partial physeal bars may develop after injury to the growth plate in children, eventually leading to disturbance of normal growth. Clinical presentation, age of the patient, and the anticipated growth will dictate the best treatment strategy. The ideal treatment for a partial physeal bar is complete excision to allow growth resumption by the remaining healthy physis. There are countless surgical options, some technically challenging, that must be weighted according to each case’s particularities. We reviewed the current literature on physeal bars while reporting the challenging case of a short stature child submitted to a femoral physeal bar endoscopic-assisted resection with successful growth resumption. This case dares surgeons to consider all options when treating limb length discrepancy, such as the endoscopic-assisted resection which might offer successful results.