bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1292: ProTALKS: A community outreach project founded by a graduate of the CaRE2 Community Scientist Research Advocacy training program, Mrs. Lynn Jones-Turpin
Authors: Jones-Turpin Lynn , Guzman Ileana , Hensel Brooke , Webb Fern
Published: March 2024

ProTALKS was created and led by a community member committed to reducing prostate cancer health disparities. ProTALKS stands for Prostate Cancer Outreach, Opinions, and Opportunities and is designed to increase awareness of prostate cancer prevention, research, and treatment as well as highlight the health disparities observed in Black communities. According to the Florida Department of Health, prostate cancer incidence and mortality rates among Black men living in Duval County are higher compared to men of other races and ethnicities. Therefore, there is a need for programs like ProTALKS that focus on early detection strategies and promoting community resources. In collaboration with the Prostate Health Education Network (PHEN), The American Legion Post 197, and Florida Blue, ProTALKS has increased access to services such as prostate cancer screening and evidence-based information. Community events implemented by ProTALKS bring together oncologists, researchers, key community leaders, health educators, and providers to educate and promote positive health behavior changes among high-risk communities. In addition to hosting health fairs, ProTalks has hosted grilling competitions and community awareness walks to further educate the community about prostate cancer prevention, screening, and research. ProTALKS also shares information through the local newspaper, The Jacksonville Free Press, The Lynn & Friends radio show, and social media platforms. Since its start in 2021, with support from the Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center, ProTALKS has implemented more than 10 community events with over 1,000 community members from Jacksonville, Florida. ProTALKS, in collaboration with CaRE2, continues to disseminate information about cancer screening, the importance of clinical trial participation, and donating biospecimens for cancer research. Although ProTALKS has been successful in its mission, there have been challenges throughout its implementation. For example, one challenge has been increasing the number of community members attending events and using appropriate marketing techniques to promote ProTALKS’ activities. Future implications to avoid challenges include recruiting more volunteers, and partnering with other community organizations in Duval County.

Citation Format: Lynn Jones-Turpin, Ileana Guzman, Brooke Hensel, Fern Webb. ProTALKS: A community outreach project founded by a graduate of the CaRE2 Community Scientist Research Advocacy training program, Mrs. Lynn Jones-Turpin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1292.
Abstract 1310: Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with prostate cancer
Authors: Kaninjing Ernest , Asiedu Gladys , Van Voorhis Kaitlin , Young Mary Ellen , Erefah Ebenezer , Agboola Emmanuel , Odedina Folakemi , Dronca Roxana , Ashing Kimlin , Rotimi Solomon , Ngufor Che , Merriweather Arnola , McCall John , Hill Anthony
Published: March 2024

Background: Sub-Saharan African Immigrants (SSAI) represent one of the fastest-growing segments of the immigrant population in the United States (US). Between 2010 and 2018, the SSAI population in the US increased by 53%, significantly outpacing the 12% growth rate for the overall foreign-born population in the US during that time frame. Despite these growing numbers, little is published about the extent to which SSAIs adapt to health behaviors more common in the US or remain immersed in the values, beliefs and practices reflective of their country of origin. Importantly, no study has comprehensively examined the Social Determinants of Health (SDOH) among this population relative to their migration experiences and their influence on health-seeking behaviors and decision-making regarding prostate cancer care and treatment options.

Methods: This qualitative study employed grounded theory and the social determinants of migrant heath framework to better understand the needs of SSAI prostate cancer survivors in the United States and how to effectively support these survivors. In-depth interviews were conducted with 8 survivors who live in the states of Florida and Minnesota.

Findings: Some participants reported limited access to care and financial challenges paying for drugs. In terms of coping with diagnosis and treatment, most of the participants relied on their faith, a positive outlook about survivorship and support of family members. Some participants relied on the coaching and support of a loved one who experienced prostate cancer in the past. Erectile dysfunction severely impacted the sexual life of most participants as they experienced difficulty getting an erection.

Conclusion: Participants expressed the benefit of belonging to support groups with other survivors for social and emotional support. As the number of immigrants from sub-Saharan continue to rise, so too will the demand for culturally tailored care to address and reduce disparities in survivorship among this sub-population.

Citation Format: Ernest Kaninjing, Gladys Asiedu, Kaitlin Van Voorhis, Mary Ellen Young, Ebenezer Erefah, Emmanuel Agboola, Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Solomon Rotimi, Che Ngufor, Arnola Merriweather, John McCall, Anthony Hill. Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1310.
Abstract 1313: Racial disparities in colorectal cancer incidence across US ethnic groups: A comprehensive analysis
Authors: Chaudhuri Anathbandhu , Gray Rosianna
Published: March 2024

Colorectal cancer (CRC) ranks as the third most prevalent global cancer and the fourth leading cause of cancer-related deaths. Racial disparities in CRC within the United States pose a significant public health concern, affecting incidence, mortality rates, and screening rates. This study investigates the impact of racial disparities on CRC incidence across various US states, utilizing CRC data from the National Cancer Institute (NCI) at the Centers for Disease Control and Prevention (CDC). Analysis with GraphPad Prism 5 software and Student's t-test reveals a consistent trend of higher CRC incidence in males compared to females, irrespective of ethnicity. Notably, the Black and American Indian ethnic groups demonstrate the highest CRC incidences among all races, especially in individuals aged 65 and above. Certain states, including Iowa and Mississippi for Black populations, and Alaska, Minnesota, Montana, Oklahoma, and South Dakota for American Indian populations, exhibit significantly elevated CRC incidences compared to the national average. County-specific analysis in Alabama reveals varying CRC incidence rates across ethnic groups, with higher rates in specific counties, such as Clarke County for Black males. Limited reports for American Indian, Asian Pacific, and Hispanic ethnic groups indicate potential disparities in access to testing, awareness, and funding for CRC detection and prevention. This study concludes that Black and American Indian males and females experience a higher incidence of colorectal cancer, possibly influenced by genetic factors or other variables contributing to CRC development. The observed disparities are multifaceted, arising from a combination of social, economic, and healthcare system factors. Addressing these complexities is crucial for mitigating CRC disparities and promoting equitable healthcare access and outcomes. Additional research, including molecular screening studies, is essential to substantiate disparities in cancer-related health and enhance public health and cancer awareness within the community.

Key Words: Cancer, Colorectal Cancer, Health Care, Racial Disparities

Citation Format: Anathbandhu Chaudhuri, Rosianna Gray. Racial disparities in colorectal cancer incidence across US ethnic groups: A comprehensive analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1313.
Abstract 1325: CD19 CAR-expressing iPSC-derived NK cells effectively enhance migration and cytotoxicity into glioblastoma by targeting to the pericytes in tumor microenvironment
Authors: Kong Dasom , Kwon Daekee , Moon Bokyung , Kim Da-Hyun , Kang Kyung-Sun
Published: March 2024

In cancer immunotherapy, targeting specific antigens with chimeric antigen receptors (CARs) has emerged as a potent tool for cell-based therapy. After being accessed by CARs, the selective anticancer lysis by CAR-natural killer (NK) cells through ‘missing-self’ and ‘induced-self’ mechanisms can mitigate off-tumor toxicity, a contrast to CAR-T cells. This specificity can be advantageous in the heterogeneous milieu of solid tumors. In the tumor microenvironment of glioblastoma (GBM), pericytes not only support tumor growth but also contribute to immune evasion, underscoring their potential as therapeutic targets in GBM treatment. Indeed, we examined and observed the presence of CD19-positive pericytes derived from GBM in patient samples, particularly within the perivascular niche, highlighting CD19 as a possible therapeutic target. Given this context, our study aimed to target the GBM tumor microenvironment, with a special focus on pericytes expressing CD19, to evaluate the potential effectiveness of CD19 CAR-iNK cells against GBM. In this study, we generated induced pluripotent stem cell-derived NK (iNK) cells with CD19 CAR. To determine whether CD19 CAR targets the tumor microenvironment pericytes in GBM, we developed GBM-blood vessel assembloids (GBVA) by fusing GBM spheroids with blood vessel organoids. When co-cultured with GBVA, CD19 CAR-iNK cells migrated towards the pericytes surrounding the GBM, inducing tumor lysis through NKp44 upregulation. Using a microfluidic chip, we observed that post-infused CD19 CAR-iNK cells targeted pericytes in a perfusion-like setting, facilitating an examination of CD19 CAR-driven migration and their tumor-specific cytotoxicity on the GBM. Therefore, we conclude that CD19 CAR-iNK cells may effectively target the pericytes in the GBM tumor microenvironment, suggesting their potential therapeutic value for GBM treatment.

Citation Format: Dasom Kong, Daekee Kwon, Bokyung Moon, Da-Hyun Kim, Kyung-Sun Kang. CD19 CAR-expressing iPSC-derived NK cells effectively enhance migration and cytotoxicity into glioblastoma by targeting to the pericytes in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1325.
Abstract 1350: KD6001: A promising new anti-CTLA-4 human monoclonal antibody for cancer therapy
Authors: Chen Yi , Li Peng , Fang Guobo , Wu Heng , Zhang Chi , Cai Zeling
Published: March 2024

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that negatively regulates T cell activation. Inhibiting this negative regulation through CTLA-4 blockade has emerged as a promising therapeutic strategy against cancer. Herein, we present the preclinical pharmacology study of KD6001, a novel anti-CTLA-4 IgG1 kappa human monoclonal antibody with superior properties compared to ipilimumab, a currently approved anti-CTLA-4 mAb. Surface plasmon resonance (SPR) analysis revealed that KD6001 exhibits a higher affinity for CTLA-4 compared to ipilimumab (KD = 0.57 nM vs 1.20 nM). Competition ELISA experiments demonstrated that KD6001 is significantly more potent than ipilimumab in disrupting CTLA-4 interactions with CD80 (IC50 = 16 ng/mL vs 93 ng/mL) and CD86. Further, amino acid point mutation analysis indicated that two specific residues following the CD80/CD86 binding site (99MYPPPY104) are critical for ipilimumab binding, whereas mutation of the two residues had minimal impact on KD6001's CTLA-4 binding activity. These findings suggest that KD6001 and ipilimumab bind distinct epitopes on CTLA-4. In vitro experiments demonstrated that KD6001 enhances the production of IL-2 and IFNγ in PHA-activated human lymphocytes and exhibits synergistic anti-tumor effects when combined with anti-PD-1/L1 antibodies. Moreover, in vivo studies utilizing syngeneic murine tumor models established in human CTLA-4 gene knock-in mice revealed that KD6001 effectively inhibits or delays tumor growth in colon cancer MC38, melanoma B16, and hepatocellular carcinoma Hepa1-6 models. Additionally, KD6001 demonstrated synergistic anti-tumor effects when combined with a mouse anti-PD-1 antibody or ibuprofen. Toxicity evaluation in cynomolgus monkeys revealed that KD6001 was generally well-tolerated at doses ranging from 1 mg/kg to 10 mg/kg administered intravenously once weekly for four weeks. The primary pathological changes observed were lymphocyte/monocyte infiltration or increased lymphocyte/monocyte infiltration in several organs, consistent with KD6001's mechanism of action. Notably, the similar affinity of KD6001 for human and cynomolgus monkey CTLA-4 suggests that the toxicity profile observed in monkeys accurately reflects the dose-toxicity relationship in human. The promising preclinical data presented herein support the further clinical development of KD6001 as a potential therapeutic agent for cancer treatment. Currently, clinical trials evaluating KD6001 in patients with advanced melanoma are ongoing.

Citation Format: Yi Chen, Peng Li, Guobo Fang, Heng Wu, Chi Zhang, Zeling Cai. KD6001: A promising new anti-CTLA-4 human monoclonal antibody for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1350.
Abstract 1407: Investigating the effect of an aged liver microenvironment on immune surveillance and predisposition to cancer​
Authors: Gandhi Armin Aabish , Hoffmann Filipe Araujo , II Michael LaPorte , Havas Aaron , Rajesh Adarsh , Davis Andrew , Teneche Marcos G. , Proulx Jessica , Kaech Susan , Adams Peter D.
Published: March 2024

The incidence of liver cancer is increasing and there is an urgent need for new therapies and preventative strategies. Age is a major risk factor for liver cancer, the reasons for which are not well defined. One of the hallmarks of aging is immune dysfunction which affects liver homeostasis potentially making it prone to cancer. To understand the role of immune dysfunction in aging liver, we analyzed immune cells from young and old livers. As is reported before, in aged livers we observed an increase in CD101+PD1+CD8+ T cell population as well as an increase in an IFNγ+TNFα+ population suggesting an increase in T cell response in an aging liver. We next sought to understand the cause of T cell exhaustion in aged livers. Cell cluster analysis of the young (4-month-old) and old (22 month old) livers by scRNA seq revealed a cell population unique to the aged livers, showing increased expression of immune checkpoint ligands as well as tumor-initiating cell markers. We validated this data by flow cytometry. We next functionally probed the immune environment of aged liver, by testing the effect of cognate antigen expression in young and old hepatocytes on adoptively transferred activated P14 CD8+ T cells isolated from a young P14 mouse. Analysis of the ex vivo activated P14 CD8+ T cells from young and old antigen-expressing livers by flow cytometry and scRNA sequencing revealed increased exhaustion and cytokine-deficiency in old mice as compared to the young mice. This study explores the age-associated alterations in the immune cells in the liver, aiming to alter liver-resident immune cells and their metabolic states in a way that promotes anti-tumor immunity in an aging liver.

Citation Format: Armin Aabish Gandhi, Filipe Araujo Hoffmann, Michael LaPorte II, Aaron Havas, Adarsh Rajesh, Andrew Davis, Marcos G. Teneche, Jessica Proulx, Susan Kaech, Peter D. Adams. Investigating the effect of an aged liver microenvironment on immune surveillance and predisposition to cancer​ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1407.
Abstract 1408: Intrahepatic IgA complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of HCC
Authors: Sung Pil Soo
Published: March 2024

Background and Aims: Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play key roles in the tumor microenvironment (TME). Immunoglobulin A (IgA) contributes to inflammation and anti-tumor immunity dismantling in the human liver. We investigated the effects of the IgA complex on CAFs in the TME of hepatocellular carcinoma (HCC).

Approach and Results: CAF dynamics in HCC TME were analyzed via single-cell RNA sequencing of HCC samples. CAFs were isolated from 40 HCC samples. The isolated CAFs were treated with mock or serum-derived IgA dimers. Following treatment with the mock or serum IgA dimers in vitro, co-culture experiments were performed using CAF and CD8+ T cells. Single-cell analysis showed that sub-cluster proportions in the CAF-fibroblast activation protein-α (FAP) matrix were significantly increased in patients with high serum IgA levels. We were performed flow cytometry on fresh surgical tissues and observed a significant increase in the mean fluorescence intensity (MFI) of FAP in the CD68+ cells from patients with high serum IgA levels compared to those with low serum IgA levels (p<0.001). We validated that the transferrin receptor (CD71) is expressed in CAFs (p<0.01). IgA-treated CAFs exhibited higher programmed death-ligand 1 (PD-L1) expression levels than mock-treated CAFs (p<0.05). Co-culture with CAFs induced the attenuation of the cytotoxic function of activated CD8+ T cell, and these cells co-cultured with IgA-treated CAFs exhibited increased expression levels of programmed death-1 (PD-1) compared to those co-cultured with mock-treated CAFs (p<0.05).

Conclusions: Intrahepatic IgA induces polarization of HCC CAFs into more malignant matrix phenotype and attenuates cytotoxic T cell function. Our study uncovers five dynamic CAF subpopulations within HCC tissues and highlights their potential roles in tumor progression and immune suppression.

Citation Format: Pil Soo Sung. Intrahepatic IgA complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1408.
Abstract 1419: Locoregional delivery with engineered stem cells modulates immunosuppressive tumor microenvironment in brain leptomeningeal metastasis
Authors: Kanaya Nobuhiko , Seddiq Waleed , Chen Kok-Siong , Kajiwara Yoshinori , Lama Lucia Moreno , Kuroda Shinji , Fujiwara Toshiyoshi , Wakimoto Hiroaki , Shah Khalid
Published: March 2024

Leptomeningeal metastasis (LM) is one of the severe disease conditions in brain metastasis (BM) and results in poor prognosis and reduction of quality of life. Immunotherapies such as anti-Programmed cell Death (PD)-1 antibodies have shown improved overall survival against non-small cell lung cancer (NSCLC).. However, the clinical benefit of patients with NSCLC derived LM is still limited due to poor penetration of therapeutic agents into the brain and cerebrospinal fluid (CSF) and lack of understanding of the tumor microenvironment in LM. In this study, we first developed immune-competent mouse models of LM which show significantly decreased immune cells and increased PD-1+ T cells in the tumor microenvironment as compared to primary NSCLC tumors, thus mimicking primary and LM NSCL in patients. Next, we explored the use of oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit an antitumor effect via oncolysis and production of neoantigens for targeting LM NSCLC. Given that virus neutralization, and inefficient extravasation are the major barriers to the effective systemic delivery of oHSV to target metastatic tumor lesions in the brain, we utilized mesenchymal stem cells (SC) and created two population of mesenchymal SC types: one for loading oncolytic herpes simplex virus (oHSV) and another one, engineered with knockout of Nectin-1 receptor by CRISPR/Cas9 technique to be resistant to oHSV, for secreting single-chain variable fragment (scFv) anti-PD-1. We show that locoregional treatment improved therapeutic outcomes by inducing oHSV-mediated immunogenic cell death, and activation of anti-tumor T cell signaling in mouse NSCLC LM tumors. Our novel SCs based immunotherapeutic strategy provides a roadmap towards treatment of lung to brain leptomeningeal metastatic patients.

Citation Format: Nobuhiko Kanaya, Waleed Seddiq, Kok-Siong Chen, Yoshinori Kajiwara, Lucia Moreno Lama, Shinji Kuroda, Toshiyoshi Fujiwara, Hiroaki Wakimoto, Khalid Shah. Locoregional delivery with engineered stem cells modulates immunosuppressive tumor microenvironment in brain leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1419.
Abstract 1479: ABCC3 (MRP3)-mediated export of deoxycholic acid regulates MAPK signaling in colorectal adenoma and adenocarcinoma
Authors: Sato Yukihiro , Kobayashi Minoru , Ohira Masahiro , Funayama Ryo , Maekawa Masamitsu , Karasawa Hideaki , Ohnuma Shinobu , Unno Michiaki , Nakayama Keiko
Published: March 2024

ABCC3 (also known as MRP3) is an ATP binding cassette transporter and it works as a bile acids transporter. We previously elucidated that ABCC3 expression is downregulated in colorectal cancer through the Wnt/β-catenin signaling pathway. However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We here explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. First, we performed experiments with clinical samples of familial adenomatous polyposis (FAP) patients to confirm whether ABCC3 expression is already downregulated in colorectal adenomas. Next, we investigated the effect of ABCC3 expression on intracellular bile acid concentrations using ABCC3 knockdown and overexpression colorectal cancer cell lines (HT-29, SW620). The intracellular concentration of deoxycholic acid, which is known to have carcinogenic effects, was verified with fluorescently labeled deoxycholic acid. Then, we tested whether activation of oncogenic signaling by deoxycholic acid is affected by ABCC3 expression changes. Finally, we examined the effect of nonsteroidal anti-inflammatory drugs (NSAIDs), which have been suggested to inhibit the carcinogenesis of FAP, on the expression of ABCC3 in experiments with colorectal cancer cell lines. Gene and protein expression analysis of colorectal adenomas isolated from FAP patients revealed that ABCC3 were downregulated as early as at the stage of adenoma formation, and many other genes related to bile acid efflux were also downregulated. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid in colorectal cancer cells, respectively. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that several NSAIDs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of FAP. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling.

Citation Format: Yukihiro Sato, Minoru Kobayashi, Masahiro Ohira, Ryo Funayama, Masamitsu Maekawa, Hideaki Karasawa, Shinobu Ohnuma, Michiaki Unno, Keiko Nakayama. ABCC3 (MRP3)-mediated export of deoxycholic acid regulates MAPK signaling in colorectal adenoma and adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1479.
Abstract 1492: Unveiling the re-programming of choroid plexus and leptomeningeal metastasis
Authors: Nobre Ana Rita , Wang Helen , Estrera Rachel , Osei-Gyening Isaiah , Boire Adrienne
Published: March 2024

Leptomeningeal metastasis (LM) is an increasingly common, fatal complication of breast and lung cancer. Despite aggressive treatment, neurologic deficits accumulate rapidly, and patients generally succumb to LM within months. We must expand our limited mechanistic knowledge of this disease.

Under homeostatic conditions, choroid plexus (ChP), highly vascularized structures within the brain ventricles, restrict the entry of macromolecules and cells into the leptomeninges; however, select cancer cells can cross this barrier and grow within the leptomeningeal space. We hypothesize that interactions between cancer and ChP niche cells alter both the niche and the cancer cells, ultimately supporting LM.During neurogenesis, the ChP display substantial extracellular matrix (ECM) remodeling, which is elegantly modulated by dynamic spatiotemporal regulation of MMPs, Wnt signaling, among other effector proteins. Similarly, 2-photon imaging of ChP collected from mice harboring LM revealed a profound ECM remodeling of the ChP when compared with naïve mice. This remodeling was accompanied by increased levels of MMP2 and MMP9 in LM mice. Upon pharmacological inhibition of MMP2 and MMP9 in vivo, we observed a decrease in LM burden and increase in overall survival, which correlates with a decrease in ChP permeability. Interestingly, human CSF from patients with leptomeningeal metastases is also enriched in collagen 1 fragments, MMP2, MMP9 and TIMP1. TIMP1, a MMP9 natural inhibitor, is not present in complex with MMP9, suggesting a role of TIMP1 as a cytokine in LM progression. TIMP1 neutralization and knockout from the cancer cells leads to a decrease in LM burden and increase in overall survival. Together, these data suggest a provocative link between proteolysis and inflammation in LM progression.

The use of clinically-annotated human samples and mouse models of LM, and the integration of transcriptomics and proteomics enabled us to identify key signaling pathways, and capture the re-programming of ChP niche and cancer cells that unlock the leptomeningeal space to cancer cells. The timeframe for this evolution will be further revealed by analysis of mouse and human samples at different stages of cancer progression.

Citation Format: Ana Rita Nobre, Helen Wang, Rachel Estrera, Isaiah Osei-Gyening, Adrienne Boire. Unveiling the re-programming of choroid plexus and leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1492.
Abstract 1499: Senescent stromal cells drive lung metastases of breast cancer
Authors: Melam Anupama , Ye Jiayu , Stewart Sheila A.
Published: March 2024

In 2022 in the United States, there were nearly 300,000 women diagnosed with breast cancer (BC) with the risk increasing significantly after age 50. The overall 5-year survival rate dramatically decreases, from 99% for patients with stage I, to a devastating 25% for those with stage IV (metastatic) BC, making distal metastasis the leading cause of BC mortality. This mortality rate has not changed in decades with lungs being one of the most common sites for distal metastasis of BC. The BC microenvironment is a complex mix, consisting of tumor cells and numerous nontumor cells including distinct subpopulations of cancer-associated fibroblasts (CAFs): vascular (vCAFs), inflammatory (iCAFs), and myofibroblastic CAFs (myCAFs), which can play pro- or anti-tumor roles. Senescent fibroblasts, which accumulate with age typically express p16INK4A and can modulate the cells around them via the secretion of a cadre of pro-tumorigenic factors including cytokines, chemokines, and extracellular matrix (ECM) modulating enzymes, collectively called the senescence-associated secretory phenotype (SASP). To investigate how p16+ senescent cells impact tumorigenesis, we mated the well-characterized MMTV-PyMT mouse, to the INK-ATTAC (INK) mouse, wherein treatment with AP20187 (AP) selectively eliminates p16+ senescent cells. Preliminary data showed that elimination of p16+ aSMA+ senescent fibroblasts (senCAF) resulted in a significant decrease in primary tumors, lung tumor foci and lung metastatic burden. Further, we found that senescent CAFs (senCAFs) were the only stromal cells eliminated in the PyMT-INK mouse treated with AP, suggesting that this CAF subtype is a key contributor to tumor progression. To determine if senCAFs directly impacted lung metastasis, EO771-LG Luc mammary tumor cells were injected in the tail vein of INKATTAC mice that were treated with AP to eliminate p16+ senCAFs. We found that metastatic tumor burdens were significantly reduced in INK+ versus control mice and immunohistochemical analysis revealed that tumor burden and foci was significantly reduced, suggesting that senCAFs in the lung promoted tumor cell seeding and outgrowth.

Citation Format: Anupama Melam, Jiayu Ye, Sheila A. Stewart. Senescent stromal cells drive lung metastases of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1499.
Abstract 1520: A novel cluster of cytolytic alpha/beta TCR+CD4−CD8−T cells originating from CD8+T cells with potent innate-like T cell killing ability: implicating adoptive T cell transfer therapy for hepatocellular carcinoma
Authors: Wu Cheng-Heng , Tseng Te-Wei , Huang Chen-Yang , Ou Ping-Hsun , Lin Yi-Chen , Chen Pin-Jung , Lin Po-Ting , Yang Chan-Keng , Teng Wei , Wu Tsung-Han , Lin Yung-Chang , Lin Chun-Yen
Published: March 2024

Tumor immunotherapies represent promising strategies for treating various cancers, including hepatocellular carcinoma. In this context, immune cells, including the adoptive T cell transfer treatment, become the focus of interests. Notably, alpha/beta TCR+CD4−CD8−T (DNT) cells is a subgroup of T cells that is ignored for a long time but was re-focused recently. These DNT cells are a group of cells with opposite functions in different condition, including pro-inflammatory or suppressive functions and possibly originated from over-stimulation of peripheral CD4+T cells/CD8+T cells or a special group of T cells formed in thymus. In our research results, we have found these DNT cells increased in murine hepatoma model, especially in the tumor microenvironment. In addition, these DNT cells from tumor microenvironment of murine hepatoma possessed potent tumor-killing ability. Furthermore, we analyzed the transcriptome profile of T cells in tumor microenvironment by single cell RNAseq approach (CITE-seq). We found DNT cells could be categorized into two main clusters, one is cytolytic DNT cells, resemble the potent CD8+T cells, and another is the CD4+T cell-like DNT cells. These cytolytic DNT cells are not exhausted but with high expression of cytolytic molecule and low hypoxia-inducible factor-1alpha (HIF-1a) expression. By trajectory analysis, cytolytic DNT cells come from the conventional CD8+T cells but following a unique developmental pathway that is different from the exhausted CD8+T cells. Interesting, these cytolytic DNT cells also expressed high level of Fcer1g molecule, a marker of innate CD8+T cells. In addition, these DNT cells could be generated and expanded in-vitro by IL-15 without TCR activation. In conclusion, we identified a cluster of cytolytic DNT cells, originated from CD8+T cells, exhibits innate T cells behavior and potent killing ability. In addition, these cytolytic DNT cells could be generated and expanded in-vitro for the adoptive T cell transfer treatment of hepatoma.

Citation Format: Cheng-Heng Wu, Te-Wei Tseng, Chen-Yang Huang, Ping-Hsun Ou, Yi-Chen Lin, Pin-Jung Chen, Po-Ting Lin, Chan-Keng Yang, Wei Teng, Tsung-Han Wu, Yung-Chang Lin, Chun-Yen Lin. A novel cluster of cytolytic alpha/beta TCR+CD4−CD8−T cells originating from CD8+T cells with potent innate-like T cell killing ability: implicating adoptive T cell transfer therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1520.
Abstract 1535: Differential immune microenvironments in triple-negative breast cancer and hormone receptor-positive HER2-negative breast cancer: A spatial analysis via multiplex immunofluorescence
Authors: Cha Yoon Jin , Park Inho , Shin Su-Jin
Published: March 2024

Objective: To elucidate differences in immune cell (IC) composition and their spatial distribution between triple-negative breast cancer (TNBC) and hormone receptor-positive HER2-negative breast cancer (HR+HER2-BC), and to evaluate the effect of PD-L1 status on these parameters.

Methods: We selected 32 patients with ≥60% tumor-infiltrating lymphocytes (TIL) (TNBC, n=18; HR+HER2- BC, n=14). Multiplex immunofluorescence was employed on resected tumor tissues. Using markers such as CK, CD20, CD8, CD4, and FOXP3, IC types and tumor cells (TC) were identified in both stromal and tumor areas. We analyzed and compared cellular density and proportional distribution of IC, and spatial interactions (both IC-TC and IC-IC) based on tumor subtype and PD-L1 status.

Results: TNBC exhibited a unique IC composition with a higher proportion of CD8+IC (stroma: 27% vs 17%, p<0.001; tumor: 54% vs 31%, p<0.001) and CD4+FOXP3+IC (stroma: 3.9% vs 3.0%, p=0.036) than HR+HER2-BC. Among PD-L1 positive cases, TNBC had a denser stromal population of CD4+FOXP3+IC (146.4±67.1/mm2 vs 114.3±146.9/mm2, p=0.036). Both tumor subtypes displayed varied IC compositions based on PD-L1 status. Density plots revealed a pronounced clustering of IC near TC in TNBC, especially in PD-L1 positive cases. Analysis of cell-cell interactions showed diverse adjacency patterns between TC and various IC combinations with frequencies differing by tumor subtype and PD-L1 status.

Conclusion: The immune landscape, typified by IC composition and spatial distribution, varies between TNBC and HR+HER2- BC, with PD-L1 status further modulating these patterns.

Citation Format: Yoon Jin Cha, Inho Park, Su-Jin Shin. Differential immune microenvironments in triple-negative breast cancer and hormone receptor-positive HER2-negative breast cancer: A spatial analysis via multiplex immunofluorescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1535.
Abstract 1551: Succinyl-CoA synthetase Beta-A: A novel metastasis promoting factor in lung cancer
Authors: Kang Jihoon , Hwang Jung Seok , Boese Austin C. , Shuff Sydney , Kim Jaehyun , Eun Kiyoung , Kang Sumin
Published: March 2024

Changes in metabolism occur when cancer cells disseminate from primary sites and metastasize. Mitochondrial metabolism plays an essential role in various biological processes of cancer cells, but the underlying mechanism through which mitochondrial factors contribute to cancer metastasis remains largely elusive. Anoikis is a form of apoptosis induced by loss of cell adhesion, and metastatic tumor cells must be anoikis resistant to survive during circulation before forming metastatic foci in distant organs. We performed an unbiased RNAi screen using a customized mitochondrion shRNA library and identified succinyl-CoA synthetase beta-A (A-SCS, also called SUCLA2), which is known to catalyze the reversible conversion of succinyl-CoA and ADP to succinate and ATP in the TCA cycle as an essential factor that promotes the survival of disseminated cancer cells during metastasis. We demonstrate that A-SCS manages redox balance during tumor metastasis, and this metabolic contribution is independent of its role in the TCA cycle. Mechanistically, A-SCS relocates from the mitochondria to the cytosol and binds to stress granules, promoting stress granules to express the redox-scavenging enzyme catalase upon cell detachment. This mitigates oxidative stress and makes cancer cells survive through anoikis, eventually promoting metastasis. A clinical correlation study comparing primary and metastasized tumors collected from lung cancer patients demonstrated that A-SCS levels align with catalase expression as well as the metastatic progression of lung cancer. Our finding provides an academic basis for developing new treatment targets against metastasis, which strikes elevated mitochondrial metabolism during cancer cell dissemination.

Citation Format: Jihoon Kang, Jung Seok Hwang, Austin C. Boese, Sydney Shuff, Jaehyun Kim, Kiyoung Eun, Sumin Kang. Succinyl-CoA synthetase Beta-A: A novel metastasis promoting factor in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1551.
Abstract 1556: AMIGO2 is associated with the peritoneal dissemination in serous ovarian cancer by enhancing its adhesion to peritoneal mesothelial cells
Authors: Iida Yuki , Sato Shinya , Yamamoto Koji , Hikino Kohei , Okawa Masayo , Hosokawa Masayo , Sawada Mayumi , Komatsu Hiroaki , Kudoh Akiko , Seong Hee Kyung , Izutsu Runa , Osaki Mitsuhiko , Okada Futoshi , Taniguchi Fuminori
Published: March 2024

Amphoterin-induced gene and open reading frame 2 (AMIGO2) has been associated with the prognosis of colorectal, gastric, and cervical cancer. However, its relationship with ovarian cancer remains unclear. This study aimed to clarify the role of AMIGO2 in ovarian cancer. The research involved evaluating AMIGO2 expression in patients with ovarian serous carcinoma using immunohistochemistry. The AMIGO2-high group exhibited significantly shorter progression-free survival (PFS) compared to the AMIGO2-low group. The predictive index of the AMIGO2-high group was considerably higher than that of the AMIGO2-low group. The rate of complete cytoreductive surgery was lower in the AMIGO2-high group than in the AMIGO2-low group. Furthermore, in vitro studies showed that four serous ovarian cancer cell lines expressed AMIGO2 expression and adhesion to mesothelial cells. Adhesion to mesothelial cells was attenuated by AMIGO2 knockdown in SKOV3 cells. Moreover, in a murine model, AMIGO2 downregulation in SKOV3 cells significantly suppressed peritoneal dissemination. These findings suggest that high AMIGO2 expression in serous ovarian carcinoma cells contributes to a poor prognosis by promoting peritoneal metastasis through enhanced cell adhesion to mesothelial cells.

Citation Format: Yuki Iida, Shinya Sato, Koji Yamamoto, Kohei Hikino, Masayo Okawa, Masayo Hosokawa, Mayumi Sawada, Hiroaki Komatsu, Akiko Kudoh, Hee Kyung Seong, Runa Izutsu, Mitsuhiko Osaki, Futoshi Okada, Fuminori Taniguchi. AMIGO2 is associated with the peritoneal dissemination in serous ovarian cancer by enhancing its adhesion to peritoneal mesothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1556.
Abstract 16: CD4+ and CD8+ TCRαβ-deficient bioluminescent reporter T cells for screening and characterization of neoantigen-specific TCRs
Authors: Cong Mei , Grailer Jamison , Slater Michael , Stecha Pete , Hartnett Jim
Published: March 2024

Adoptive antigen-specific T cell therapy is currently comprised of chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells. Clinical results from CAR-T cells have demonstrated promising results in treating leukemias, while TCR-engineered T cells, which have the advantage of recognizing intracellular tumor antigens, is still in early development. Here, we report the development of CD4+ or CD8+ TCRαβ-KO reporter T cell lines for the screening and characterization of transgenic TCRs. A TCRαβ-KO reporter T cell line was first developed by knocking out the endogenous TCR α and β chains in the reporter T cell line using CRISPR/Cas9. Successful knockout was confirmed by phenotypic assays and TCR v chain locus sequencing. We demonstrated that re-introduction of influenza hemagglutinin (HA) peptide-specific TCR (HA1.7) α and β chains into TCRαβ-KO reporter T cell lines results in HA peptide-dependent TCR activation and luciferase reporter expression when HA peptide is presented by a MHCII+ cell line. Similarly, re-introduction of MART-1-specific TCR (DMF5) resulted in MART-1-dependent activation in the presence of MHCI+ cells. The select expression of CD4- or CD8-expressing variants of the TCRαβ-KO reporter T cell line enables the development of transgenic TCRs for both MHCI- and MHCII-restricted tumor antigen targets. Further development of CD4/CD8 double-positive and double-negative cell lines enables screening of low and high affinity TCRs without MHC bias. Together, this TCRαβ-KO platform represents a powerful tool for the screening and characterization of neoantigen-specific TCRs.

Citation Format: Mei Cong, Jamison Grailer, Michael Slater, Pete Stecha, Jim Hartnett. CD4+ and CD8+ TCRαβ-deficient bioluminescent reporter T cells for screening and characterization of neoantigen-specific TCRs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 16.
Abstract 161: Aged mice decelerate bone metastasis of prostate cancer by decreasing infiltration of M2 macrophages
Authors: Zhang Xiao , Yu Wei , Huang Xin , Lu Yi , Zhang Jian
Published: March 2024

Bone metastasis is a major contributor to the mortality of patients with prostate cancer and results in the development of an immunosuppressive microenvironment in the bone marrow. While advanced age increases the risk of bone metastasis, effects of age-related changes on immune microenvironmental homeostasis are not yet clearly understood. To investigate interactions between cancer cells and the immune microenvironment in elderly individuals, we utilized murine-derived specific bone metastatic prostate cancer cells (RM1-BM), which we had previously isolated from bone metastatic mice and transfected with a luciferase-based reporter gene. We then injected the cells into the left ventricle of both 3‒6 months and 22‒24 months, male, wild-type mice to induce bone metastasis, using age-matched mice injected with PBS as a control. We employed in vivo imaging to compare the metastatic levels in both groups of mice every other day. On day 14, we extracted bone marrow cells for CyTOF analysis and femurs and tibias for Hematoxylin and Eosin staining. Interestingly, our preliminary results demonstrated that healthy aged mice exhibited a lower susceptibility to develop bone metastasis when compared to their younger counterparts. A further investigation of the immune subtypes revealed an increase in the percentage of macrophages in CD45+ immune cells in young mice that developed bone metastasis as opposed to age-matched controls. However, the percentage decreased in aged mice, going from 12.20% to 9.92% (p = 0.001). Lastly, macrophages were isolated from the bone marrow of 3‒6 months and 22‒24 months old mice and were co-cultured with ovalbumin-transfected RM1-BM cells (RM1-BM-ova) in vitro for 24 hours. The flow cytometry results indicated that both groups consist mainly of CD206+ (M2) macrophages. Nonetheless, those obtained from aged mice exhibited reduced ovalbumin presentation capability while maintaining a steady level of type I major histocompatibility complex (MHC-I). These findings suggested that increased infiltration of pro-inflammatory M2 macrophages within the tumor microenvironment may contribute to the bone metastasis of prostate cancer. Therefore, inhibiting M2 macrophages recruitment to the bone marrow microenvironment may prove a useful approach for treating patients with prostate cancer bone metastasis. This study was supported by the NSFC projects (81972420, 81972766, 82173336), and grants from the Shenzhen Science and Technology Innovation Commission (JCYJ20190809161811237, JCYJ20210324104214040).

Citation Format: Xiao Zhang, Wei Yu, Xin Huang, Yi Lu, Jian Zhang. Aged mice decelerate bone metastasis of prostate cancer by decreasing infiltration of M2 macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 161.
Abstract 1680: Roles of EphA2 receptor signaling in prostate cancer development and progression
Authors: Lingerak Ryan , Petty Aaron , Guo Hong , Lin Hebei , Shi Xiaojun , Kim Soyeon , Wang Bingcheng
Published: March 2024

Aggressive forms of prostate cancer (PCa), while initially responsive to androgen deprivation therapy (ADT), inevitably become resistant to therapy and are considered castration resistant PCa (CRPC). A major goal of PCa research has been to broadly identify molecular and cellular mechanisms that aid this progression to identify potential therapeutic targets. Using a combination of human data and unique animal models, we found that the receptor tyrosine kinase (RTK) EphA2 is overexpressed specifically in castration resistant and advancing prostate cancers. Furthermore we show that in metastatic PCa the receptor undergoes ligand-independent oncogenic signaling mediated by phosphorylation of EphA2 at S897. Together our data indicate a potential mechanism in PCa progression in which EphA2 becomes overexpressed and aids acquisition of castration resistance via acting as a driver of cell migration, invasion, and proliferation.

Citation Format: Ryan Lingerak, Aaron Petty, Hong Guo, Hebei Lin, Xiaojun Shi, Soyeon Kim, Bingcheng Wang. Roles of EphA2 receptor signaling in prostate cancer development and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1680.