bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA09: Mapping myeloid programs that control tumor immunity
Authors: Merad Miriam 
Published: January 2022

Abstract
Immune checkpoints blockade established the proof of principle that activating T effector immune function can significantly improve cancer outcome. However, the majority of patients fail to respond to checkpoint blockade therapy, likely because in many patients, suppressive mechanisms cannot be overcome with checkpoint blockade alone. T cells effector programs are instructed and modulated by professional antigen presenting cells (APC) that populate tumor lesions. Yet very little is known about the molecular wiring of APC in the tumor microenvironment. Here we used CITE-Seq to profile 600,000 immune cells in tumor and adjacent tumor-free tissues from 35 patients with lung cancer lesions. We also used CITE-Seq to profile APC that reside in experimental lung cancer lesions. We identified the molecular profile of APC that accumulate in tumors compared to the adjacent tissues and explored the functional relevance of these programs in experimental lung cancers. We show that most APC co-express both immunogenic and suppressive pathways that reduce their functionality in tissues. Specifically, we found that Th2 cytokines produced by tumor cells significantly contribute to limiting APC immunogenicity and to promoting APC -driven immunoregulation of T cell and NK cell effector function in the tumor microenvironment. These data emphasize the benefit of blocking Th2 response in epithelial tumors to enhance APC functionality and promote antitumor immunity.
Citation Format: Miriam Merad. Mapping myeloid programs that control tumor immunity [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA09.
Abstract IA20: What does not kill it makes it stronger: Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy
Authors: Obenauf Anna C. 
Published: January 2022

Abstract
Targeted therapies and immunotherapies represent main pillars of cancer treatment, yet how they shape tumours during treatment response and resistance and thereby influence subsequent therapeutic responses is poorly understood. Here, we show in melanoma patients and mouse models that when tumours relapse on targeted MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite their entirely different mode of action. We find that cross-resistance is mediated via a cancer cell-instructed, immune-suppressive tumour microenvironment that lacks functional CD103+ dendritic cells, precluding an effective T cell response. Restoration of CD103+ dendritic cell numbers and functionality can re-sensitize cross-resistant tumours to immunotherapy. Using our lineage tracing method CaTCH, which allows the retrospective isolation of founding clones prior to evolutionary selection, we demonstrate that cross-resistance is acquired during MAPKi treatment. Cross-resistance does not arise from the selective pressure of an immune response during the evolution of resistance, paradoxically it results from the MAPK pathway, which is not only reactivated during the formation of targeted therapy resistance but has gained increased transcriptional output driving immune evasion. Our work provides mechanistic evidence for cross-resistance between unrelated therapies and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy.
Citation Format: Anna C. Obenauf. What does not kill it makes it stronger: Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA20.
Abstract P010: Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors
Authors: Burger Megan L. , Cruz Amanda M. , Crossland Grace E. , Gaglia Giorgio , Ritch Cecily C. , Blatt Sarah E. , Bhutkar Arjun , Tavana Sara Z. , Santagata Sandro , Jacks Tyler 
Published: January 2022

Abstract
CD8 T cell responses against different tumor neoantigens occur simultaneously, yet it is unclear whether they interact to potentiate or antagonize the overall anti-tumor response. In a genetically engineered mouse model of lung adenocarcinoma, we find that antigen dominance hierarchies are established in tumors wherein the antigen that most stably binds MHC dominates the CD8 T cell response. This negatively impacts the response to subdominant antigens, suppressing T cell expansion, differentiation and effector function; a phenotype that is reversed when the dominant antigen is removed. Intriguingly, the subdominant response is also enriched for a TCF1+ progenitor cell phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, we find that the subdominant response does not preferentially benefit from ICB due to predominance of a dysfunctional subset of TCF1+ cells marked by CCR6 expression and differentiation to a Tc17 phenotype. CCR6+ TCF1+ cells are also found broadly across human cancers and do not correlate with patient response to ICB. This subset appears to be derived from poor T cell receptor stimulation, due to competition of T cells for good interactions with antigen presenting cells. Vaccination eliminates CCR6+ TCF1+ cells and disrupts the antigen dominance hierarchy, preferentially expanding the subdominant CD8 T cell response in tumors. Overall enrichment of TCF1+ cells is maintained amongst the subdominant response post-vaccination and current studies are exploring whether this promotes more durable tumor control or better response to ICB. These findings provide strong rationale for evaluating the relative response to high versus low pMHC stability antigens in clinical trials of pooled neoantigen vaccines, where low stability, subdominant antigens may contribute more to tumor control than previously realized.
Citation Format: Megan L. Burger, Amanda M. Cruz, Grace E. Crossland, Giorgio Gaglia, Cecily C. Ritch, Sarah E. Blatt, Arjun Bhutkar, Sara Z. Tavana, Sandro Santagata, Tyler Jacks. Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P010.
Abstract P016: Circulation immune landscape in canonical pathogenesis of colorectal cancer by CyTOF analysis
Authors: Ding Ke-Feng , Kong Xiang-Xing , Xu Jia-Sheng , Jiao Yu-Rong , Hu Ye-Ting , Xiao Qian , Hao Xu-Ran , Gao Zong-Bao , Li Jun 
Published: January 2022

Abstract
Objective: The present study aims to firstly describe the circulation immune landscape in the canonical pathogenesis of colorectal cancer (CRC) by detecting the peripheral white blood cell using mass cytometry by time-of-flight (CyTOF) technology.
Methods: A total of 42 healthy controls (HC), 47 colorectal adenoma (CRA) patients, and 102 CRC patients were enrolled and their pathological information were also collected. A panel of 42 cell surface antigen markers were detected by mass spectrometry flow cytometry after peripheral blood mononuclear cells (PBMC) separated. The expression differences of various cell subsets among the three groups were further compared, and the cell subsets with different expressions were screened out for in-depth analysis.
Results: We annotated the PBMC as T cells, B cells, NK cells and myeloid cells, and performed identification and component comparison of cell subgroups respectively. Compared with HC and CRA, NKT cell subsets were significantly reduced in CRC, while Naïve CD4+ T cells, effector CD8+ T cells and central memory CD8+ T cells were increased. Compared with HC, Treg cells increased in CRA, and central memory CD4+ T increased in CRC; but Naïve CD8+ T cells and Naïve double-negative T (DNT) cells decreased in both CRA and CRC. Compared with HC and CRA, Naïve B cells were significantly decreased in CRC; but switched memory B cells were increased. CD16- NK cells were significantly higher in CRC while CD16+ NK cells were decreased compared with HC. CD16- monocytes were increased, but CD16+ monocytes were decreased in CRC when compared to HC. Basophils and monocytes were significantly increased in CRC compared to CRA. Furthermore, we also found Effector CD4+ T cells and Naïve B cells increased during lymph node metastasis, while unswitched B cells, plasmablast and basophils decreased.
Conclusion: We had successfully described the immune landscape of the canonical pathogenesis of CRC, and we further analyzed the changes in cell subsets related to the occurrence of lymphatic metastasis.
Citation Format: Ke-Feng Ding, Xiang-Xing Kong, Jia-Sheng Xu, Yu-Rong Jiao, Ye-Ting Hu, Qian Xiao, Xu-Ran Hao, Zong-Bao Gao, Jun Li. Circulation immune landscape in canonical pathogenesis of colorectal cancer by CyTOF analysis [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P016.
Abstract P032: Expression of an IL-15 receptor fusion protein enhances the persistence of TRuC-T cells
Authors: Fleury Michelle , Anderson Courtney , Watt Amy , Horton Holly , Zieba Adam , Ding Jian , Tighe Robert , Hofmeister Robert , McCarthy Derrick , Gutierrez Dario 
Published: January 2022

Abstract
Adoptive cell therapies have shown great promise in hematological malignancies. To realize the potential of T cell therapies in solid tumors, we have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes all TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin-targeting TRuC-T cells (aka TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the effector function and persistence of TRuC-T cells in the hostile tumor microenvironment, we generated TC-210 T cells that express a membrane-tethered IL15Rα-IL15 fusion protein. IL-15 is a common γ chain cytokine that promotes the differentiation, maintenance, and effector function of memory CD8+ T cell subsets and confers resistance to IL-2-mediated activation induced cell death (AICD). In vitro, the co-expression of the IL-15 fusion protein enhances T cell proliferation and persistence upon repeated stimulation with MSLN+ cancer cell lines, while exhaustion marker expression is decreased. Furthermore, IL-15 enhanced TC-210 T cells sustain a significantly higher TCF-1+ population. When tested in a mesothelioma xenograft mouse model, the presence of the IL-15 fusion protein increased tumor infiltration and persistence of TC-210 T cells. Altogether, the presented data support clinical studies that explore the impact of IL-15 enhancement on the persistence of TC-210 T cells and depth of response in patients with MSLN+ malignancies.
Citation Format: Michelle Fleury, Courtney Anderson, Amy Watt, Holly Horton, Adam Zieba, Jian Ding, Robert Tighe, Robert Hofmeister, Derrick McCarthy, Dario Gutierrez. Expression of an IL-15 receptor fusion protein enhances the persistence of TRuC-T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P032.
Abstract P036: A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs
Authors: Huntington Kelsey E. , Louie Anna , Zhou Lanlan , El-Deiry Wafik S. 
Published: January 2022

Abstract
Inflammatory cytokines, immune stimulants, chemokines, and tumor growth/growth suppressing factors are molecular messengers that circulate and have the capability to modify the tumor microenvironment and impact response to therapeutics. The characterization of soluble mediators as biomarkers for diagnosis and prognosis is of interest in oncology. We utilize the cytokinome to characterize the response of colorectal tumor cell lines to selected small-molecules in oncology as a proof-of-concept dataset with immune synergy heat map rankings of analytes for drug and cell line combinations. We observed overall trends in drug-class effects with MEK-, BRAF-, PARP-inhibitors, and Imipridones in cytokine, chemokine, and growth factor responses that may help guide therapy selection. MEK-inhibitor treatment downregulated analytes VEGF, CXCL9/MIG, and IL-8/CXCL8 and upregulated CXCL14/BRAK, Prolactin, and CCL5/RANTES. BRAF-inhibitor treatment downregulated VEGF and IL-8/CXCL8, while increasing sTRAIL-R2. Treatment with PARP-inhibitors decreased CXCL9/MIG, IL-8/CXCL8, CCL3/MIP-1 alpha, VEGF, and CXCL14/BRAK, while treatment increased sTRAIL-R2 and prolactin. Treatment with Imipridones decreased CCL3/MIP-1 alpha, VEGF, CXCL14/BRAK, IL-8/CXCL8, and Prolactin and increased CXCL5/ENA-78. We also observed differential responses to therapeutics depending on the mutational profile of the cell line. In the future, a similar but larger data-set may be utilized in the clinic to aid in immune synergy prediction of a patient's response to therapy based on tumor genotype.
Citation Format: Kelsey E. Huntington, Anna Louie, Lanlan Zhou, Wafik S. El-Deiry. A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P036.
Abstract P038: Identification and functional evaluation of monoclonal antibodies specifically targeting human Carbonic Anhydrase IX
Authors: Lenferink Anne E. G. , Baardsnes Jason , Sulea Traian , Wu Cunle , Acchione Maurizio , Jaramillo Maria L. , McDonald Paul C. , Benard Francois , Dedhar Shoukat 
Published: January 2022

Abstract
Poor vascularization of solid tumors leads to inadequate nutrient and oxygen supplies which forces tumor cells to reprogram their metabolism. Consequently, the tumor cell's environment becomes acidic and hypoxic. This triggers signaling cascades involving e.g. heterodimeric hypoxia-inducible factor (HIF). Activation of this hypoxia-induced transcriptional program is crucial for the tumor cell to survive its hostile microenvironment and its ability to metastasize. One of the genes HIF upregulated is carbonic anhydrase (CA)-IX (CAIX, gene G250/MN-encoded transmembrane protein). CA-IX catalyzes carbon dioxide (CO2) thereby generating a proton (H+) and bicarbonate (HCO3−), the latter of which is transported back into the cell and utilized to help safeguard intracellular pH (pHi) stability. Except for the stomach and the gallbladder, CA-IX expression is negligible in normal tissues. In contrast, a broad range of tumors express high levels of CA-IX, where the protein can serve as a biomarker for the early stages of tumor development but also as tumor marker of hypoxia associated with resistance to chemotherapy and radiotherapy. Preclinical and clinical studies have shown that CA-IX is a promising therapeutic target for detection and therapy for several cancer types. To date only a limited number of ant-CAIX monoclonal antibodies (mAbs) have been available for clinical testing as therapeutic and imaging agents. In the current study, we generated and functionally categorized a panel of 51 mouse mAbs that specifically bind to human CA-IX. Characterization of the mAbs revealed that of the mAbs with the best biophysical characteristics, three (3) mAbs are suitable as an antibody-drug conjugate (ADC), two (2) mAbs inhibit the CA-IX enzyme activity, and one (1) mAb that is suitable for CA-IX imaging purposes. These preliminary data presented here could thus form the basis for the development of novel CA-IX targeted immunotherapies and diagnostic tools for the treatment of cancer.
Citation Format: Anne E. G. Lenferink, Jason Baardsnes, Traian Sulea, Cunle Wu, Maurizio Acchione, Maria L. Jaramillo, Paul C. McDonald, Francois Benard, Shoukat Dedhar. Identification and functional evaluation of monoclonal antibodies specifically targeting human Carbonic Anhydrase IX [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P038.
Abstract P067: Current status of regulatory-approved immunotherapies in Saudi Arabia
Authors: Ajina Reham 
Published: January 2022

Abstract
Immunotherapy has been shown to successfully turn aggressive malignancies in many patients into curable diseases. Thus, immunotherapy has received so much attention internationally, and Saudi Arabia was not an exception. Here, we evaluated the status of regulatory-approved immunotherapies in Saudi Arabia using the Saudi Food and Drug Administration (sFDA) database and the ClinicalTrials.gov website. We found that not all available immunotherapies in the clinic worldwide are approved by the sFDA, and the number of Saudi immunotherapy clinical trials are very limited. In fact, out of the eight regulatory-approved immune checkpoint inhibitors, 5 have received the sFDA approval. These immune check point inhibitors are Yervoy (ipilimumab), Nivolumab (Opdivo), Pembrolizumab (Keytruda), Atezolizumab (Tecentriq) and Avelumab (Bavencio). Also, out of the 5 regulatory approved chimeric antigen receptor (CAR) T cell therapy products, only KYMRIAHTM (tisagenlecleucel) has received the sFDA approval. According to the ClinicalTrials.gov registry (accessed 27 July 2021), only 6 investigational clinical trials have been conducted in Saudi Arabia to evaluate immune check point inhibitors, and only 3 of these studies are currently ongoing. More surprisingly, no Saudi CAR clinical trials have yet been conducted. Taken together, there is an urgent need for a greater accessibility for immunotherapy in the country.
Citation Format: Reham Ajina. Current status of regulatory-approved immunotherapies in Saudi Arabia [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P067.
Abstract P069: Semi-automated validation and quantification of CTLA-4 in 90 different Tumor entities using multiple antibodies and artificial intelligence
Authors: Dum David , Henke Tjark L. C. , Mandelkow Tim , Bady Elena , Raedler Jonas B. , Simon Ronald , Sauter Guido , Lennartz Maximilian , Wilczak Waldemar , Burandt Eike , Steurer Stefan , Blessin Niclas C. 
Published: January 2022

Abstract
Introduction: CTLA-4 is an inhibitory immune checkpoint receptor and a negative regulator of anti-tumor T-cell function. This study aimed at a comparative analysis of CTLA-4+ cells between different tumor entities.
Methods: To quantify CTLA-4+ cells, 4,582 tumor samples from 90 different tumor entities as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Two different antibody clones (MSVA-152R and CAL49) were validated and quantified using a deep learning framework for automated exclusion of unspecific immunostaining.
Results: Comparing both CTLA-4 antibodies revealed a clone dependent cytoplasmic cross-reactivity in adrenal cortical adenoma (63%) for MSVA-152R and in pheochromocytoma (67%) as well as hepatocellular carcinoma (36%) for CAL49. After automated exclusion of non-specific staining reaction (3.6%), a strong correlation was observed for the densities of CTLA-4+ lymphocytes obtained by both antibodies (r=0.87; p&lt;0.0001). The mean density of CTLA-4+ cells was 674±1482 cells/mm2 and ranged from 71±175 cells/mm2 in leiomyoma to 5916±3826 cells/mm2 in Hodgkin's lymphoma. Within epithelial tumors, the density of CTLA-4+ lymphocytes were higher in squamous cell (421±467 cells/mm2) and urothelial carcinomas (419±347 cells/mm2) than in adenocarcinomas (269±375 cells/mm2) and renal cell neoplasms (256±269 cells/mm2). A high CTLA-4+ cell density was linked to low pT category (p&lt;0.0001), absent lymph node metastases (p=0.0354), and PD-L1 expression in tumor cells or inflammatory cells (p&lt;0.0001 each). A high CTLA-4/CD3-ratio was linked to absent lymph node metastases (p=0.0295) and to PD-L1 positivity on immune cells (p&lt;0.0026).
Conclusion: Marked differences exist in the number of CTLA-4+ lymphocytes between tumors. Analyzing two independent antibodies by a deep learning framework identifies clone-specific cross-reactivity and facilitates automated quantification of target proteins such as CTLA-4.
Citation Format: David Dum, Tjark L. C. Henke, Tim Mandelkow, Elena Bady, Jonas B. Raedler, Ronald Simon, Guido Sauter, Maximilian Lennartz, Waldemar Wilczak, Eike Burandt, Stefan Steurer, Niclas C. Blessin. Semi-automated validation and quantification of CTLA-4 in 90 different Tumor entities using multiple antibodies and artificial intelligence [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P069.
Abstract PR06: Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity
Authors: Pylayeva-Gupta Yuliya , Mirlekar Bhalchandra 
Published: January 2022

Abstract
B cells frequently infiltrate human tumors, and the intra-tumoral abundance of plasma cells can correlate with improved patient prognosis. While substantial evidence documents the presence of both regulatory B cells (Breg) and effector B cells, there is a significant knowledge gap in our understanding of how pro- versus anti-tumor B cell responses are generated and whether such responses are interconnected and/or amenable to re-programming. We report the existence of a negative regulatory signaling network that reprograms naïve B cells in pancreatic cancer to antagonize anti-tumor plasma B cells. This network is driven by IL-35-mediated STAT3 activation, which directly stimulates upregulation of the pioneer transcription factors Pax5 and Bcl6 in naïve B cells and impedes plasma cell differentiation while simultaneously activating regulatory B cell phenotypes. Significantly, inhibition of Bcl6 reversed this tumor-associated reprogramming of naïve B cells, enabling intratumoral accumulation of plasma cells, and reduced tumor growth. Our data provide evidence that the balance between Breg and plasma cell is the key to tumor immunity. B cell dysfunction in cancer involves a potentially targetable suppression program that alters the differentiation potential of naïve B cells.
Citation Format: Yuliya Pylayeva-Gupta, Bhalchandra Mirlekar. Reprogramming of naïve B cells in pancreatic cancer subverts humoral immunity [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR06.