bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR011: Histone demethylase KDM5D drives sex-specific differences in colorectal cancer
Authors: Li Jiexi , Lan Zhengdao , Liao Wenting , Horner James W. , Liu Jielin , Jiang Shan , Shim Hong S. , Slotnik Max , LaBella Kyle A. , Hsu Wen-Hao , Spring Denise J. , Wang Y. Alan , DePinho Ronald A. 
Published: December 2022

Abstract
Gender exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible oncogenic Kras transgene (KRAS*) and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with KRAS* CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of epithelial cell tight junction and MHC class I complex components. Deletion of KDM5D in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive KDM5D expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, thus providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
Citation Format: Jiexi Li, Zhengdao Lan, Wenting Liao, James W. Horner, Jielin Liu, Shan Jiang, Hong S. Shim, Max Slotnik, Kyle A. LaBella, Wen-Hao Hsu, Denise J. Spring, Y. Alan Wang, Ronald A. DePinho. Histone demethylase KDM5D drives sex-specific differences in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR011.
Abstract A09: Immune checkpoint inhibitor-induced polyarthritis: a case series
Authors: Smith-Uffen Megan , Tselios Konstantinos 
Published: December 2022

Abstract
Background. Immune checkpoint inhibitors (ICIs) have revolutionized cancer care. However, their mechanism of action also results in the uncontrolled collateral of ICI-related adverse events (ICI-AEs). Polyarthritis is a rare ICI-AE. Here we describe two cases of ICI-induced polyarthritis, induced by nivolumab/ipilimumab and sasanlimab for melanoma and urothelial cancer, respectively. Methods/Results. A 64-year-old male received combination immunotherapy with nivolumab and ipilimumab for metastatic melanoma. Within one month of his second cycle of nivolumab alone, he developed polyarthritis of the small joints of the hands bilaterally, as well as the shoulders and knees; active synovitis; and erosive arthropathy on radiographic findings. He was successfully treated with prednisone at 20mg daily, gradually tapered over several months. A 43-year-old male with high-grade non-invasive urothelial cell carcinoma received two cycles of adjuvant sasanlimab. Within two months of his second treatment, he developed a large-joint polyarthritis involving the bilateral knees, ankles, elbows, and the cervical spine. His symptoms resolved with prednisone, initiated at 50mg daily with a recommended slow taper, however resurfaced five days after he abruptly ceased treatment. He was subsequently started on methotrexate in combination with prednisone. Both patients had a past medical history of non-rheumatological autoimmune disease, developed symptoms within 8 weeks of ICI, had elevated inflammatory markers and negative autoantibodies. Neither had to discontinue their cancer therapy and indeed both had a good tumour responses to their ICI. Both of our patients were initially well-managed prednisone. However, our second patient relapsed after abrupt cessation of his prednisone and required a combination of methotrexate with prednisone to control his symptoms. Conclusions. These cases add to the literature on ICI-induced polyarthritis, a rare ICI-AE. Clinical manifestations most commonly resemble rheumatoid arthritis, with bilateral inflammation of the small joints. Time to onset tends to be &lt;12 weeks after ICI exposure, and repeated ICI exposure is a risk factor. Most patients have no personal or family history of autoimmune disease, negative autoantibodies, and can be managed well with glucocorticoids. As ICIs become more widely used, rheumatologists and oncologists alike should familiarise themselves with their adverse effects. More research is needed to understand the epidemiology, clinical presentation, and treatment of these adverse events.
Citation Format: Megan Smith-Uffen, Konstantinos Tselios. Immune checkpoint inhibitor-induced polyarthritis: a case series [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A09.
Abstract A10: In vivo CRISPR screen reveals how to drive therapeutic T cell function to solid tumors
Authors: Hong Yeonsun , Kim Minsoo 
Published: December 2022

Abstract
Chimeric antigen receptor (CAR)-T cell therapy is emerging as a promising option for cancer immunotherapy. Although CAR-T cell therapy has excellent efficacy in the treatment of hematologic malignancies, it has largely failed in patients with solid tumors due to several problems, such as homing and trafficking. Here, we performed an in vivo targeted CRISPR-Cas9 screens to identify a molecular regulator of off-target trafficking of CAR-T cells, and identified ST3 b-galactoside a-2,3-sialyltransferase1 (St3gal1) as a major negative factor of CAR-T cells migration. Analysis of Maackia amurensis lectin-II immunoprecipitates revealed that CD18 in activated CD8+ T cells is the glycoproteins bearing the St3gal1-specific α2,3-sialylated glycans. Overexpression of St3gal1 in activated T cells induced glycosylation of lymphocyte function-associated antigen-1 (LFA-1), which inhibited endocytic recycling of LFA-1, leading to the nonspecific accumulation of T cells in the lungs. We checked that the expression of St3gal1 increased, and that of bII-spectrin, a key LFA-1 associated cytoskeleton molecule, decreased as T cells were activated. Engineered CAR-T cells with enhanced bII-spectrin expression showed decreased St3gal1 expression and induced a significant reduction in tumor growth in mice through improved tumor-specific homing. In addition, the expression level of bII-spectrinin anti-CD19 CAR-T cells injected in patients with large B-cell lymphomas correlated positively with patient response to treatment but negatively with systemic toxicity. Our findings suggest that St3gal1-bII-spectrin axis controls tissue-specific migration of therapeutic T cells delivered intravenously, which can improve tumor-specific homing of CAR-T cells in cancer immunotherapy.
Citation Format: Yeonsun Hong, Minsoo Kim. In vivo CRISPR screen reveals how to drive therapeutic T cell function to solid tumors [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A10.
Abstract A15: Interaction between cancer-associated fibroblasts and apoptotic cancer cells inhibits the migration and invasion of lung cancer cells and cancer-associated fibroblasts preventing the development of metastasis
Authors: Kim Hee Ja , Yang Kyungwon , Kim Kiyoon , Kang Jihee Lee 
Published: December 2022

Abstract
The interplay between apoptotic cancer cells and the tumor microenvironment (TME) modulates cancer progression and metastasis. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting these events through paracrine communication. In the present study, we investigated how the interaction of CAFs with apoptotic lung cancer cells modulates migration and invasion of cancer cells and CAFs. CAFs isolated from the lung tumors of Kras-mutant (KrasLA1) mice and ultraviolet-irradiated apoptotic cancer cells, including 344SQ (murine), A549 and HCT116 cells (human), were used for Transwell migration and invasion assays. Western blotting, real-time quantitative PCR, immunofluorescence staining, cytokine array, ELISA, and flow cytometry were used to assess TGFβ1 signaling pathways, CAF activation markers, Notch1 signaling pathways and phagocytosis. For in vivo study, apoptotic 344SQ cells with or without the Notch1 inhibitor LY3039478 were injected following subcutaneously injection of 344SQ cells into syngeneic (129/Sv) mice. In addition, conditioned medium (CM) derived from CAFs with or without neutralizing mouse anti-WISP-1 antibody or isotype IgG was administered via intratumoral injection. Interaction of lung CAFs and apoptotic cancer cells suppressed TGFb1-induced migration and invasion of cancer cells and CAFs. Enhanced secretion of Wnt-induced signaling protein 1 (WISP-1) by CAFs exposed to apoptotic 344SQ cells (ApoSQ) was required for these anti-migration and -invasion effects. Pharmacologic inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the anti-migration and -invasion effects. In addition, a single injection of ApoSQ enhanced WISP-1 production, suppressed expression of CAF activation markers in isolated Thy1+ CAFs, and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling. Treatment with ApoSQ-exposed CAF CM suppressed lung metastasis, whereas WISP-1-immunodepleted ApoSQ-exposed CAF CM reversed the anti-metastatic effect.
Citation Format: Hee Ja Kim, Kyungwon Yang, Kiyoon Kim, Jihee Lee Kang. Interaction between cancer-associated fibroblasts and apoptotic cancer cells inhibits the migration and invasion of lung cancer cells and cancer-associated fibroblasts preventing the development of metastasis [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A15.
Abstract A16: RIG-I-mediated cell death pathways activated by PAMP RNA in hepatic tumor cells
Authors: Ulloa Brittany , Gale Michael 
Published: December 2022

Abstract
Most malignant cells are poorly immunogenic and fail to elicit an effective antitumor response. However, some viral infections of cancer cells can trigger intracellular innate immune defenses that initiate cancer cell death, known as “oncolytic signaling.” Our lab has identified a viral pathogen associated molecular pattern (PAMP) RNA motif from the hepatitis C virus (HCV) genome that is recognized by the pathogen recognition receptor, retinoic acid-inducible gene I (RIG-I), to induce innate immune signaling when delivered to cells in a liposomal formulation. We found that PAMP RNA can direct RIG-I-dependent signaling to drive cell death in tumor cells, indicating that PAMP activation of the RIG-I pathway has applications for oncolytic destruction of tumors. However, the exact cell death pathways that are activated by PAMP are not clearly defined. We hypothesize that PAMP activates a RIG-I-mediated form of apoptosis and that cancer cells are more susceptible than non-cancer cells to death by this apoptotic pathway. In vitro studies using CRISPR knockout cell lines confirmed that PAMP-induced cell death signaling requires RIG-I, mitochondrial antiviral-signaling protein (MAVS), and interferon regulatory factor 3 (IRF3). Further, our analyses show that PAMP-induced cell death is regulated by type 1 interferon, and that cell death outcomes can be blocked by treatment of cells with caspase inhibitor. Thus, PAMP-induced RIG-I signaling triggers cell death through linkage with caspase signaling. This research will define cell death pathways activated by PAMP and RIG-I signaling by interrogating multiple cell death programs and will reveal the potential of designing antitumor therapeutics leveraging PAMP.
Citation Format: Brittany Ulloa, Michael Gale. RIG-I-mediated cell death pathways activated by PAMP RNA in hepatic tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A16.
Abstract A21: Virtual clinical trials: a tool for identifying patients who benefit from treatment beyond progression with pembrolizumab in NSCLC
Authors: Qi Timothy , Cao Yanguang 
Published: December 2022

Abstract
Background: Enrolling patients in immunotherapy clinical trials is becoming increasingly competitive. Virtual clinical trials can help investigators answer key questions despite this. For example, pembrolizumab is the recommended first-line treatment for non-small cell lung cancer (NSCLC) with no driver alterations and PD-L1 Tumor Proportion Score (TPS) ≥ 50%. Salvage therapies for relapsed/refractory patients are limited. Retrospective studies suggest a subset of patients may benefit from pembrolizumab treatment beyond progression (TBP); these results have not been validated in a prospective study. Methods: We constructed digital twins of patients and enrolled them in virtual clinical trials to identify the best salvage therapy after progressive disease (PD) on pembrolizumab. Response dynamics were evaluated at the lesion level to represent patients who experience systemic PD while individual lesions are still shrinking. With &gt; 25,000 radiographic lesion measurements from &gt; 500 patients, we simulated responses to pembrolizumab, chemotherapy, and PD on pembrolizumab followed by either pembrolizumab TBP or salvage chemotherapy. We then assessed combination pembrolizumab and chemotherapy to explore a possible mechanism of intrapatient drug synergy called lesion-level independent action (LLIA).Results: Switching all progressors to salvage chemotherapy was suboptimal. Virtual trials identified a subset of patients with fewer baseline lesions who experienced longer progression-free survival (PFS) and disease control on pembrolizumab TBP. Combination therapy under LLIA but not patient-level independent action (PLIA) yielded longer PFS.Conclusions: Pembrolizumab TBP may benefit a subset of patients with PD-L1-high, driver alteration-free NSCLC, but prospective studies are warranted. LLIA may be an important consideration for future clinical investigation.
Citation Format: Timothy Qi, Yanguang Cao. Virtual clinical trials: a tool for identifying patients who benefit from treatment beyond progression with pembrolizumab in NSCLC [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A21.
Abstract A32: GIGA-564, a third generation anti-CTLA-4 with minimal ability to block CTLA-4 binding to B7 ligands, has enhanced efficacy but reduced toxicity compared to ipilimumab in pre-clinical models
Authors: Stone Erica L , Carter Kyle P , Wagner Ellen K , Asensio Michael A , Benzie Emily , Chiang Yao Yuan , Coles Garry L , Edgar Chelsea , Gautam Bishal K , Gras Ashley , Leong Jackson , Leong Renee , Manickam Vishal A , Mizrahi Rena A , Niedecken Ariel R , Saini Jasmeen , Sandhu Savreet K , Simons Jan Fredrick , Stadtmiller Kacy , Tinsley Brendan , Tracy LaRee , Wayham Nicholas P , Lim Yoong Wearn , Adler Adam S , Johnson David S 
Published: December 2022

Abstract
Anti-CTLA-4 antibodies such as ipilimumab were among the first immuno-oncology agents to show significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients and can induce severe, immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its ligands, is the primary mechanism of action for ipilimumab. Here we present evidence that checkpoint inhibition may not be the primary mechanism of action for efficacy of anti-CTLA-4 antibodies. Instead, the primary mechanism for efficacy may be FcR-mediated Treg depletion in the tumor microenvironment. First, we identified a monoclonal antibody (mAb), GIGA-564, that binds to CTLA-4 at an epitope that differs from ipilimumab’s by only a few amino acids, yet has limited checkpoint inhibitor activity. Surprisingly, GIGA-564 has superior anti-tumor activity compared to ipilimumab in a murine model. GIGA-564 also induces less Treg proliferation and has increased ability to induce in vitro FcR signaling and in vivo depletion of intratumoral Tregs. Further experiments showed that the enhanced FcR activity of GIGA-564 likely contributes to its enhanced anti-tumor activity. Importantly, we also showed that GIGA-564 was associated with lower toxicity in murine models. Our work suggests that new anti-CTLA-4 drugs should be optimized for Treg depletion rather than checkpoint inhibition.
Citation Format: Erica L Stone, Kyle P Carter, Ellen K Wagner, Michael A Asensio, Emily Benzie, Yao Yuan Chiang, Garry L Coles, Chelsea Edgar, Bishal K Gautam, Ashley Gras, Jackson Leong, Renee Leong, Vishal A Manickam, Rena A Mizrahi, Ariel R Niedecken, Jasmeen Saini, Savreet K Sandhu, Jan Fredrick Simons, Kacy Stadtmiller, Brendan Tinsley, LaRee Tracy, Nicholas P Wayham, Yoong Wearn Lim, Adam S Adler, David S Johnson. GIGA-564, a third generation anti-CTLA-4 with minimal ability to block CTLA-4 binding to B7 ligands, has enhanced efficacy but reduced toxicity compared to ipilimumab in pre-clinical models [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A32.
Abstract A34: Therapeutic induction of High Endothelial Venules in cancer generates TCF1+ lymphocyte niches
Authors: Vella Gerlanda , Hua Yichao , Rambow Florian , Allen Elizabeth , Martinez Asier Antoranz , Merchiers Pascal , Bosisio Francesca , Floris Giuseppe , Takeda Akira , Jalkanen Sirpa , Hollmén Maija , Marine Jean-Christophe , Schlenner Susan , Bergers Gabriele 
Published: December 2022

Abstract
The lack of T-cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLS), which are the local site of humoral and cellular immune responses against cancers, are associated with good prognosis and have recently been detected in Immune Checkpoint Blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing scRNA sequencing, endothelial fate mapping, and multiplex immunohistochemistry, we demonstrate that antiangiogenic immune-modulating therapies evoke the transition of postcapillary venules into inflamed high endothelial venules (HEV), which predominantly generate permissive TA-TLS-like lymphocyte niches. These HEV+ immune niches entail PD1neg and PD1+TCF1+CD8+ progenitor cells that differentiate into cytotoxic TCF1neg TIM3+ PD1+ CD8 effector cells and migrate into the tumor core. Congruently, TU-HEV signatures correlate with response to ICB therapies in several human tumor types. In line with these observations, TU-HEVs require continuous CD8 and NK cell-derived lymphotoxin signals revealing that tumor-HEV maintenance is actively sculpted by the immune system through a feed-forward loop.
Citation Format: Gerlanda Vella, Yichao Hua, Florian Rambow, Elizabeth Allen, Asier Antoranz Martinez, Pascal Merchiers, Francesca Bosisio, Giuseppe Floris, Akira Takeda, Sirpa Jalkanen, Maija Hollmén, Jean-Christophe Marine, Susan Schlenner, Gabriele Bergers. Therapeutic induction of High Endothelial Venules in cancer generates TCF1+ lymphocyte niches [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A34.
Abstract A46: Neoantigen-driven B and T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses
Authors: Cui Can , Craft Joseph , Joshi Nikhil S. 
Published: December 2022

Abstract
CD4 T follicular helper (TFH) cells and B cells are essential components of germinal center (GC) response, but the importance and mechanisms of TFH-B cell collaborations in malignancy are unclear. The presence of TFH, B cells and GC has been associated with favorable clinical outcomes and improved therapeutic responses to checkpoint blockade immunotherapy in numerous types of solid tumors. We found enrichment of TFH cell transcriptional signature correlates with prolonged survival in lung adenocarcinoma (LUAD) individuals. To further investigate if and how TFH-B cell interactions elicit protective anti-tumor responses, we developed the KP-HELLO murine lung adenocarcinoma model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens (HEL, LCMV GP33-43/FLAG/GP61-80, and codon-Optimized mScarlet). Collaborations between tumor-specific TFH and B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells and IL-21 production requires B cells and B cell-recognized neoantigens. We demonstrated that tumor neoantigens can educate the differentiation of tumor-specific CD4 T cells and regulate their fate by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions.
Citation Format: Can Cui, Joseph Craft, Nikhil S. Joshi. Neoantigen-driven B and T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A46.