bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Silencing Fc Domains in T cell–Engaging Bispecific Antibodies Improves T-cell Trafficking and Antitumor Potency
Authors: Wang Linlin , Hoseini Sayed Shahabuddin , Xu Hong , Ponomarev Vladimir , Cheung Nai-Kong
Published: April 2023

Abstract
Bispecific antibodies (BsAb) that engage T cells bind to tumor cells via a tumor-associated antigen and to T cells through surface CD3. BsAbs have promising antitumor properties in vivo. Here, we describe the effects of Fc silencing on BsAb-driven T-cell trafficking to solid tumors. We used BsAbs specific for disialoganglioside GD2 or oncoprotein ErbB2 (HER2) and built on the IgG(L)-scFv platform with or without Fc silencing. We studied the kinetics of T-cell infiltration from blood into solid tumor masses when driven by these BsAbs. We also investigated the therapeutic efficacy of these BsAbs in two mouse models: immunodeficient mice xenografted with patient-derived GD2+ neuroblastoma or HER2+ breast cancer, and human CD3ϵ transgenic mice implanted with a GD2+ murine tumor. BsAbs built with intact Fc domain were unable to drive T cells to tumor, thereby failing to achieve an antitumor effect in mice. T cells became sequestered in lungs by myeloid cells or depleted in circulation. In contrast, when Fc function was silenced by N297A ± K322A mutations, T cells were able to infiltrate into subcutaneous solid tumors, a prerequisite for successful therapy outcome.
Data from CD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function
Authors: Mittal Deepak , Lepletier Ailin , Madore Jason , Aguilera Amelia Roman , Stannard Kimberley , Blake Stephen J. , Whitehall Vicki L.J. , Liu Cheng , Bettington Mark L. , Takeda Kazuyoshi , Long Georgina V. , Scolyer Richard A. , Lan Ruth , Siemers Nathan , Korman Alan , Teng Michele W.L. , Johnston Robert J. , Dougall William C. , Smyth Mark J.
Published: April 2023

Abstract
CD96 is a novel target for cancer immunotherapy shown to regulate NK cell effector function and metastasis. Here, we demonstrated that blocking CD96 suppressed primary tumor growth in a number of experimental mouse tumor models in a CD8+ T cell–dependent manner. DNAM-1/CD226, Batf3, IL12p35, and IFNγ were also critical, and CD96-deficient CD8+ T cells promoted greater tumor control than CD96-sufficient CD8+ T cells. The antitumor activity of anti-CD96 therapy was independent of Fc-mediated effector function and was more effective in dual combination with blockade of a number of immune checkpoints, including PD-1, PD-L1, TIGIT, and CTLA-4. We consistently observed coexpression of PD-1 with CD96 on CD8+ T lymphocytes in tumor-infiltrating leukocytes both in mouse and human cancers using mRNA analysis, flow cytometry, and multiplex IHF. The combination of anti-CD96 with anti–PD-1 increased the percentage of IFNγ-expressing CD8+ T lymphocytes. Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted in superior antitumor responses, regardless of the ability of the anti-TIGIT isotype to engage FcR. The optimal triple combination was also dependent upon CD8+ T cells and IFNγ. Overall, these data demonstrate that CD96 is an immune checkpoint on CD8+ T cells and that blocking CD96 in combination with other immune-checkpoint inhibitors is a strategy to enhance T-cell activity and suppress tumor growth.
Data from Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention
Authors: Omene Coral , Ma Lin , Moore Jade , Ouyang Haoxu , Illa-Bochaca Irineu , Chou William , Patel Manan S. , Sebastiano Christopher , Demaria Sandra , Mao Jian-Hua , Karagoz Kubra , Gatza Michael L. , Barcellos-Hoff Mary Helen
Published: April 2023

Abstract
Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. Here, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFβ. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.
Data from Melanoma Evolves Complete Immunotherapy Resistance through the Acquisition of a Hypermetabolic Phenotype
Authors: Jaiswal Ashvin R. , Liu Arthur J. , Pudakalakatti Shivanand , Dutta Prasanta , Jayaprakash Priyamvada , Bartkowiak Todd , Ager Casey R. , Wang Zhi-Qiang , Reuben Alexandre , Cooper Zachary A. , Ivan Cristina , Ju Zhenlin , Nwajei Felix , Wang Jing , Davies Michael A. , Davis R. Eric , Wargo Jennifer A. , Bhattacharya Pratip K. , Hong David S. , Curran Michael A.
Published: April 2023

Abstract
Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a “hypermetabolic” phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved T cells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus -sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype.
Data from A PSMA-Targeting CD3 Bispecific Antibody Induces Antitumor Responses that Are Enhanced by 4-1BB Costimulation
Authors: Chiu Danica , Tavaré Richard , Haber Lauric , Aina Olulanu H. , Vazzana Kristin , Ram Priyanka , Danton Makenzie , Finney Jennifer , Jalal Sumreen , Krueger Pamela , Giurleo Jason T. , Ma Dangshe , Smith Eric , Thurston Gavin , Kirshner Jessica R. , Crawford Alison
Published: April 2023

Abstract
Patients with hematologic cancers have improved outcomes after treatment with bispecific antibodies that bind to CD3 on T cells and that redirect T cells toward cancer cells. However, clinical benefit against solid tumors remains to be shown. We made a bispecific antibody that targets both the common prostate tumor–specific antigen PSMA and CD3 (PMSAxCD3) and provide evidence for tumor inhibition in several preclinical solid tumor models. Mice expressing the human extracellular regions of CD3 and PSMA were generated to examine antitumor efficacy in the presence of an intact immune system and PSMA expression in normal tissues. PSMAxCD3 accumulated in PSMA-expressing tissues and tumors as detected by immuno-PET imaging. Although PSMAxCD3 induced T-cell activation and showed antitumor efficacy in mice with low tumor burden, PSMAxCD3 lost efficacy against larger solid tumors, mirroring the difficulty of treating solid tumors in the clinic. Costimulatory receptors can enhance T-cell responses. We show here that costimulation can enhance the antitumor efficacy of PSMAxCD3. In particular, 4-1BB stimulation in combination with PSMAxCD3 enhanced T-cell activation and proliferation, boosted efficacy against larger tumors, and induced T-cell memory, leading to durable antitumor responses. The combination of CD3 bispecific antibodies and anti-4-1BB costimulation represents a therapeutic approach for the treatment of solid tumors.
Data from Development of a Clinically Relevant Reporter for Chimeric Antigen Receptor T-cell Expansion, Trafficking, and Toxicity
Authors: Sakemura Reona , Bansal Aditya , Siegler Elizabeth L. , Hefazi Mehrdad , Yang Nan , Khadka Roman H. , Newsom Alysha N. , Hansen Michael J. , Cox Michelle J. , Manriquez Roman Claudia , Schick Kendall J. , Can Ismail , Tapper Erin E. , Nevala Wendy K. , Adada Mohamad M. , Bezerra Evandro D. , Kankeu Fonkoua Lionel Aurelien , Horvei Paulina , Ruff Michael W. , Parikh Sameer A. , Pandey Mukesh K. , DeGrado Timothy R. , Suksanpaisan Lukkana , Kay Neil E. , Peng Kah-Whye , Russell Stephen J. , Kenderian Saad S.
Published: April 2023

Abstract
Although chimeric antigen receptor T (CART)–cell therapy has been successful in treating certain hematologic malignancies, wider adoption of CART-cell therapy is limited because of minimal activity in solid tumors and development of life-threatening toxicities, including cytokine release syndrome (CRS). There is a lack of a robust, clinically relevant imaging platform to monitor in vivo expansion and trafficking to tumor sites. To address this, we utilized the sodium iodide symporter (NIS) as a platform to image and track CART cells. We engineered CD19-directed and B-cell maturation antigen (BCMA)–directed CART cells to express NIS (NIS+CART19 and NIS+BCMA-CART, respectively) and tested the sensitivity of 18F-TFB-PET to detect trafficking and expansion in systemic and localized tumor models and in a CART-cell toxicity model. NIS+CART19 and NIS+BCMA-CART cells were generated through dual transduction with two vectors and demonstrated exclusive 125I uptake in vitro. 18F-TFB-PET detected NIS+CART cells in vivo to a sensitivity level of 40,000 cells. 18F-TFB-PET confirmed NIS+BCMA-CART-cell trafficking to the tumor sites in localized and systemic tumor models. In a xenograft model for CART-cell toxicity, 18F-TFB-PET revealed significant systemic uptake, correlating with CART-cell in vivo expansion, cytokine production, and development of CRS-associated clinical symptoms. NIS provides a sensitive, clinically applicable platform for CART-cell imaging with PET scan. 18F-TFB-PET detected CART-cell trafficking to tumor sites and in vivo expansion, correlating with the development of clinical and laboratory markers of CRS. These studies demonstrate a noninvasive, clinically relevant method to assess CART-cell functions in vivo.
Data from Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell–Mediated Antitumor Immune Responses
Authors: Fedoriw Andrew , Shi Leilei , O'Brien Shane , Smitheman Kimberly N. , Wang Yunfei , Hou Jiakai , Sherk Christian , Rajapurkar Satyajit , Laraio Jenny , Williams Leila J. , Xu Chunyu , Han Guangchun , Feng Qin , Bedford Mark T. , Wang Linghua , Barbash Olena , Kruger Ryan G. , Hwu Patrick , Mohammad Helai P. , Peng Weiyi
Published: April 2023

Abstract
Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I PRMTs remains uncharacterized. Here, our The Cancer Genome Atlas dataset analysis revealed that expression of type I PRMTs associated with poor clinical response and decreased immune infiltration in patients with melanoma. In cancer cell lines, inhibition of type I PRMTs induced an IFN gene signature, amplified responses to IFN and innate immune signaling, and decreased expression of the immunosuppressive cytokine VEGF. In immunocompetent mouse tumor models, including a model of T-cell exclusion that represents a common mechanism of anti–programmed cell death protein 1 (PD-1) resistance in humans, type I PRMT inhibition increased T-cell infiltration, produced durable responses dependent on CD8+ T cells, and enhanced efficacy of anti–PD-1 therapy. These data indicate that type I PRMT inhibition exhibits immunomodulatory properties and synergizes with immune checkpoint blockade (ICB) to induce durable antitumor responses in a T cell–dependent manner, suggesting that type I PRMT inhibition can potentiate an antitumor immunity in refractory settings.
Data from C3aR Signaling Inhibits NK-cell Infiltration into the Tumor Microenvironment in Mouse Models
Authors: Nandagopal Saravanan , Li Caiyun G. , Xu Yu , Sodji Quaovi H. , Graves Edward E. , Giaccia Amato J.
Published: April 2023

Abstract
Many solid tumors have low levels of cytotoxic CD56dim natural killer (NK) cells, suggesting that CD56dim NK-cell exclusion from the tumor microenvironment (TME) contributes to the decreased response rate of immunotherapy. Complement component 3a (C3a) is known for its tumor-promoting and immunosuppressive roles in solid tumors. Previous reports have implicated the involvement of the C3a receptor (C3aR) in immune cell trafficking into the TME. C3aR is predominantly expressed on the surface of activated cytotoxic NK cells, but a specific role for C3aR in NK-cell biology has not been investigated. Because solid tumors generate elevated C3a and have decreased NK-cell infiltration, we hypothesized that C3aR might play a role in cytotoxic NK-cell recruitment into the TME. Our results indicate that blocking C3aR signaling in NK cells increased NK-cell infiltration into the TME in mouse models and led to tumor regression. Because the critical lymphocyte trafficking integrin LFA-1 orchestrates the migration of activated NK cells, we wanted to gain insight into the interaction between C3aR signaling and LFA-1. Our results demonstrated that direct interaction between C3aR and LFA-1, which led to a high-affinity LFA-1 conformation, decreased NK-cell infiltration into the TME. We propose that approaches to enhance cytotoxic NK-cell infiltration into the TME, through either disrupting C3a and C3aR interaction or inhibiting the formation of high-affinity LFA-1, represent a new strategy to improve the efficiency of immunotherapy for cancer treatment.
Table S3 from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy
Authors: Kretzmer Helene , Biran Anat , Purroy Noelia , Lemvigh Camilla K. , Clement Kendell , Gruber Michaela , Gu Hongcang , Rassenti Laura , Mohammad Arman W. , Lesnick Connie , Slager Susan L. , Braggio Esteban , Shanafelt Tait D. , Kay Neil E. , Fernandes Stacey M. , Brown Jennifer R. , Wang Lili , Li Shuqiang , Livak Kenneth J. , Neuberg Donna S. , Klages Sven , Timmermann Bernd , Kipps Thomas J. , Campo Elias , Gnirke Andreas , Wu Catherine J. , Meissner Alexander
Published: April 2023

Table of correlation between time points within one sample and number of hyper- or hypomethylated CpGs for all CLL (top) and naïve and memory B cell samples (bottom)
Supplementary Figures and Legends from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy
Authors: Kretzmer Helene , Biran Anat , Purroy Noelia , Lemvigh Camilla K. , Clement Kendell , Gruber Michaela , Gu Hongcang , Rassenti Laura , Mohammad Arman W. , Lesnick Connie , Slager Susan L. , Braggio Esteban , Shanafelt Tait D. , Kay Neil E. , Fernandes Stacey M. , Brown Jennifer R. , Wang Lili , Li Shuqiang , Livak Kenneth J. , Neuberg Donna S. , Klages Sven , Timmermann Bernd , Kipps Thomas J. , Campo Elias , Gnirke Andreas , Wu Catherine J. , Meissner Alexander
Published: April 2023

Supplementary Figures 1-7 and matching legends
Figure S3 from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy
Authors: Kretzmer Helene , Biran Anat , Purroy Noelia , Lemvigh Camilla K. , Clement Kendell , Gruber Michaela , Gu Hongcang , Rassenti Laura , Mohammad Arman W. , Lesnick Connie , Slager Susan L. , Braggio Esteban , Shanafelt Tait D. , Kay Neil E. , Fernandes Stacey M. , Brown Jennifer R. , Wang Lili , Li Shuqiang , Livak Kenneth J. , Neuberg Donna S. , Klages Sven , Timmermann Bernd , Kipps Thomas J. , Campo Elias , Gnirke Andreas , Wu Catherine J. , Meissner Alexander
Published: April 2023

Methylation dynamics across CLL progression
Figure S1 from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy
Authors: Kretzmer Helene , Biran Anat , Purroy Noelia , Lemvigh Camilla K. , Clement Kendell , Gruber Michaela , Gu Hongcang , Rassenti Laura , Mohammad Arman W. , Lesnick Connie , Slager Susan L. , Braggio Esteban , Shanafelt Tait D. , Kay Neil E. , Fernandes Stacey M. , Brown Jennifer R. , Wang Lili , Li Shuqiang , Livak Kenneth J. , Neuberg Donna S. , Klages Sven , Timmermann Bernd , Kipps Thomas J. , Campo Elias , Gnirke Andreas , Wu Catherine J. , Meissner Alexander
Published: April 2023

CLL and normal B cell comparisons
Data from Sphingosine-1-Phosphate Receptor 3 Potentiates Inflammatory Programs in Normal and Leukemia Stem Cells to Promote Differentiation
Authors: Xie Stephanie Z. , Kaufmann Kerstin B. , Wang Weijia , Chan-Seng-Yue Michelle , Gan Olga I. , Laurenti Elisa , Garcia-Prat Laura , Takayanagi Shin-ichiro , Ng Stanley W.K. , Xu ChangJiang , Zeng Andy G.X. , Jin Liqing , McLeod Jessica , Wagenblast Elvin , Mitchell Amanda , Kennedy James A. , Liu Qiang , Boutzen Héléna , Kleinau Melissa , Jargstorf Joseph , Holmes Gareth , Zhang Yang , Voisin Veronique , Bader Gary D. , Wang Jean C.Y. , Hannun Yusuf A. , Luberto Chiara , Schroeder Timm , Minden Mark D. , Dick John E.
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSCs by activating stress myelopoiesis, such roles in LSCs are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator that drives myeloid differentiation and activates inflammatory programs in both HSCs and LSCs. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across cohorts of patients with AML, each with distinct phenotypic and clinical properties. S1PR3 was high in LSCs and blasts of mature myeloid samples with linkages to chemosensitivity, whereas S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.
Significance:
S1PR3 is a novel regulator of myeloid fate in normal hematopoiesis that is heterogeneously expressed in AML. S1PR3 marks a subset of less primitive AML cases with a distinct inflammatory signature and therefore has clinical implications as both a therapeutic target and a biomarker to distinguish primitive from mature AML.

See related commentary by Yang et al., p. 3.

This article is highlighted in the In This Issue feature, p. 1
Data from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy
Authors: Kretzmer Helene , Biran Anat , Purroy Noelia , Lemvigh Camilla K. , Clement Kendell , Gruber Michaela , Gu Hongcang , Rassenti Laura , Mohammad Arman W. , Lesnick Connie , Slager Susan L. , Braggio Esteban , Shanafelt Tait D. , Kay Neil E. , Fernandes Stacey M. , Brown Jennifer R. , Wang Lili , Li Shuqiang , Livak Kenneth J. , Neuberg Donna S. , Klages Sven , Timmermann Bernd , Kipps Thomas J. , Campo Elias , Gnirke Andreas , Wu Catherine J. , Meissner Alexander
Published: April 2023

Abstract
Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in preneoplastic monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state and a distinct expression profile together with MBL cells compared with normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically driven growth dynamics, and, together with its persistent presence, suggests a central role in disease onset.
Significance:
DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism.

See related commentary by Rossi, p. 6.

This article is highlighted in the In This Issue feature, p. 1
Data from NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity
Authors: Richards Rebecca M. , Zhao Feifei , Freitas Katherine A. , Parker Kevin R. , Xu Peng , Fan Amy , Sotillo Elena , Daugaard Mads , Oo Htoo Zarni , Liu Jie , Hong Wan-Jen , Sorensen Poul H. , Chang Howard Y. , Satpathy Ansuman T. , Majzner Robbie G. , Majeti Ravindra , Mackall Crystal L.
Published: April 2023

Abstract
Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR T cells engineered from a novel humanized CD93-specific binder potently kill AML in vitro and in vivo but spare hematopoietic stem and progenitor cells (HSPC). No toxicity is seen in murine models, but CD93 is expressed on human endothelial cells, and CD93 CAR T cells recognize and kill endothelial cell lines. We identify other AML CAR T-cell targets with overlapping expression on endothelial cells, especially in the context of proinflammatory cytokines. To address the challenge of endothelial-specific cross-reactivity, we provide proof of concept for NOT-gated CD93 CAR T cells that circumvent endothelial cell toxicity in a relevant model system. We also identify candidates for combinatorial targeting by profiling the transcriptome of AML and endothelial cells at baseline and after exposure to proinflammatory cytokines.
Significance:
CD93 CAR T cells eliminate AML and spare HSPCs but exert on-target, off-tumor toxicity to endothelial cells. We show coexpression of other AML targets on endothelial cells, introduce a novel NOT-gated strategy to mitigate endothelial toxicity, and demonstrate use of high-dimensional transcriptomic profiling for rational design of combinatorial immunotherapies.

See related commentary by Velasquez and Gottschalk, p. 559.

This article is highlighted in the In This Issue feature, p. 549
Data from Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses
Authors: Gargiulo Ernesto , Viry Elodie , Morande Pablo Elías , Largeot Anne , Gonder Susanne , Xian Feng , Ioannou Nikolaos , Benzarti Mohaned , Kleine Borgmann Felix Bruno , Mittelbronn Michel , Dittmar Gunnar , Nazarov Petr V. , Meiser Johannes , Stamatopoulos Basile , Ramsay Alan G. , Moussay Etienne , Paggetti Jérôme
Published: April 2023

Abstract
Small extracellular vesicle (sEV, or exosome) communication among cells in the tumor microenvironment has been modeled mainly in cell culture, whereas their relevance in cancer pathogenesis and progression in vivo is less characterized. Here we investigated cancer–microenvironment interactions in vivo using mouse models of chronic lymphocytic leukemia (CLL). sEVs isolated directly from CLL tissue were enriched in specific miRNA and immune-checkpoint ligands. Distinct molecular components of tumor-derived sEVs altered CD8+ T-cell transcriptome, proteome, and metabolome, leading to decreased functions and cell exhaustion ex vivo and in vivo. Using antagomiRs and blocking antibodies, we defined specific cargo-mediated alterations on CD8+ T cells. Abrogating sEV biogenesis by Rab27a/b knockout dramatically delayed CLL pathogenesis. This phenotype was rescued by exogenous leukemic sEV or CD8+ T-cell depletion. Finally, high expression of sEV-related genes correlated with poor outcomes in CLL patients, suggesting sEV profiling as a prognostic tool. In conclusion, sEVs shape the immune microenvironment during CLL progression.
Significance:
sEVs produced in the leukemia microenvironment impair CD8+ T-cell mediated antitumor immune response and are indispensable for leukemia progression in vivo in murine preclinical models. In addition, high expression of sEV-related genes correlated with poor survival and unfavorable clinical parameters in CLL patients.

See related commentary by Zhong and Guo, p. 5.

This article is highlighted in the In This Issue feature, p. 1
Data from TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies
Authors: Carideo Cunniff Elizabeth , Sato Yosuke , Mai Doanh , Appleman Vicky A. , Iwasaki Shinji , Kolev Vihren , Matsuda Atsushi , Shi Judy , Mochizuki Michiyo , Yoshikawa Masato , Huang Jian , Shen Luhua , Haridas Satyajeet , Shinde Vaishali , Gemski Chris , Roberts Emily R. , Ghasemi Omid , Bazzazi Hojjat , Menon Saurabh , Traore Tary , Shi Pu , Thelen Tennille D. , Conlon Joseph , Abu-Yousif Adnan O. , Arendt Christopher , Shaw Michael H. , Okaniwa Masanori
Published: April 2023

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing.
Significance:
TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.
Data from Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium
Authors: Barber Emma L. , Chen Siqi , Pineda Mario Javier , Robertson Sharon E. , Hill Emily K. , Teoh Deanna , Schilder Jeanne , O'Shea Kaitlyn L. , Kocherginsky Masha , Zhang Bin , Matei Daniela
Published: April 2023

Purpose:
The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer.
Patients and Methods:
This single-arm, open-label, multicenter phase II study enrolled patients with RECIST measurable advanced endometrial cancer. Patients could have received ≤ 1 prior platinum-based regimen and ≤ one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared with historical control rate of 50%.
Results:
A total of 46 patients were enrolled and 43 were evaluable for ORR. Median age was 66 (range: 43–86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic endometrial cancer. Patients received carboplatin AUC6, paclitaxel 175 mg/m2, and pembrolizumab 200 mg i.v. every 3 weeks for up to six cycles. ORR was 74.4% (32/43), higher than historic controls (P = 0.001). Median progression-free survival (PFS) was 10.6 months (95% confidence interval, 8.3–13.9 months). The most common grade 1–2 treatment-related adverse event (TRAE) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%), and neuropathy (13%), while the most common grade 3–4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T-cell populations at baseline in responders. The CD8+ T-cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared with nonresponders.
Conclusions:
Addition of pembrolizumab to carboplatin and paclitaxel for advanced endometrial cancer was tolerated and improved ORR compared with historical outcomes.
Significance:
The results of the study support that the combination of pembrolizumab with carboplatin and paclitaxel is well tolerated and active in patients with advanced endometrial cancer. The duration of response and the PFS were significantly longer in patients with mismatch repair deficient/microsatellite instability-high compared with mismatch repair proficient/microsatellite stable tumors. Responders to treatment tend to have enriched CD8+ T-cell and CD4+ T-cell populations among peripheral blood mononuclear cells at baseline.
Data from CD47-blocking Antibody ZL-1201 Promotes Tumor-associated Macrophage Phagocytic Activity and Enhances the Efficacy of the Therapeutic Antibodies and Chemotherapy
Authors: Cao Anthony , Yi Jiaqing , Tang Xinyan , Szeto Christopher W. , Wu Renyi , Wan Bing , Fang Xu , Li Shou , Wang Lei , Wang Lina , Li Jing , Ye Qiuping , Huang Tom , Hsu Karl , Kabbarah Omar , Zhou Haiying
Published: April 2023

Tumor-associated macrophages (TAM) are the most abundant immune cells in the tumor microenvironment. They consist of various subsets but primarily resemble the M2 macrophage phenotype. TAMs are known to promote tumor progression and are associated with poor clinical outcomes. CD47 on tumor cells and SIRPα on TAMs facilitate a “don't-eat-me” signal which prevents cancer cells from immune clearance. Therefore, blockade of the CD47–SIRPα interaction represents a promising strategy for tumor immunotherapy. Here, we present the results on ZL-1201, a differentiated and potent anti-CD47 antibody with improved hematologic safety profile compared with 5F9 benchmark. ZL-1201 enhanced phagocytosis in combination with standards of care (SoC) therapeutic antibodies in in vitro coculture systems using a panel of tumor models and differentiated macrophages, and these combinational effects are Fc dependent while potently enhancing M2 phagocytosis. In vivo xenograft studies showed that enhanced antitumor activities were seen in a variety of tumor models treated with ZL-1201 in combination with other therapeutic mAbs, and maximal antitumor activities were achieved in the presence of chemotherapy in addition to the combination of ZL-1201 with other mAbs. Moreover, tumor-infiltrating immune cells and cytokine analysis showed that ZL-1201 and chemotherapies remodel the tumor microenvironment, which increases antitumor immunity, leading to augmented antitumor efficacy when combined with mAbs.
Significance:
ZL-1201 is a novel anti-CD47 antibody that has improved hematologic safety profiles and combines with SoC, including mAbs and chemotherapies, to potently facilitate phagocytosis and antitumor efficacy.
Data from Real-world Studies Link NSAID Use to Improved Overall Lung Cancer Survival
Authors: Roszik Jason , Lee J. Jack , Wu Yi-Hung , Liu Xi , Kawakami Masanori , Kurie Jonathan M. , Belouali Anas , Boca Simina M. , Gupta Samir , Beckman Robert A. , Madhavan Subha , Dmitrovsky Ethan
Published: April 2023

Inflammation is a cancer hallmark. NSAIDs improve overall survival (OS) in certain cancers. Real-world studies explored here whether NSAIDs improve non–small cell lung cancer (NSCLC) OS. Analyses independently interrogated clinical databases from The University of Texas MD Anderson Cancer Center (MDACC cohort, 1987 to 2015; 33,162 NSCLCs and 3,033 NSAID users) and Georgetown-MedStar health system (Georgetown cohort, 2000 to 2019; 4,497 NSCLCs and 1,993 NSAID users). Structured and unstructured clinical data were extracted from electronic health records using natural language processing (NLP). Associations were made between NSAID use and NSCLC prognostic features (tobacco use, gender, race, and body mass index, BMI). NSAIDs were statistically significantly (P < 0.0001) associated with increased NSCLC survival (5-year OS 29.7% for NSAID users vs. 13.1% for nonusers) in the MDACC cohort. NSAID users gained 11.6 months over nonusers in 5-year restricted mean survival time. Stratified analysis by stage, histopathology, and multicovariable assessment substantiated benefits. NSAID users were pooled independent of NSAID type and by NSAID type. Landmark analysis excluded immortal time bias. Survival improvements (P < 0.0001) were confirmed in the Georgetown cohort. Thus, real-world NSAID usage was independently associated with increased NSCLC survival in the MDACC and Georgetown cohorts. Findings were confirmed by landmark analyses and NSAID type. The OS benefits persisted despite tobacco use and did not depend on gender, race, or BMI (MDACC cohort, P < 0.0001). These real-world findings could guide future NSAID lung cancer randomized trials.
Significance:
NLP and real-world studies conducted in large cohorts explored whether NSAIDs improved survival across NSCLC stages, histopathology, gender, smoking history, or demographic groups. A statistically significant association between NSAID use and NSCLC survival was found. This provides a rationale for future NSAID randomized NSCLC trials.
Data from An Informatics Bridge to Improve the Design and Efficiency of Phase I Clinical Trials for Anticancer Drug Combinations
Authors: Wang Lei , Wei Lai , Zhang Shijun , Cheng Lijun , Shendre Aditi , Carson Williams , Chen James L. , Owen Dwight , Gregory Megan , Li Lang
Published: April 2023

In this study, we summarized critical databases of drug combination toxicity and pharmacokinetics. We further conducted a feasibility and utility study that demonstrates how different data sources can contribute to and assist phase I trial designs. Single-drug and drug combination toxicity and pharmacokinetic data were primarily reviewed from several databases. We focused on the MTD, dose-limiting toxicity (DLT), toxicity, and pharmacokinetic profiles. To demonstrate the feasibility and utility of these data sources in improving trial designs, phase I studies reported in ClincalTrials.gov from January 1, 2018 to December 31, 2018 were used as examples. We evaluated whether and how these studies could have been designed differently given toxicity and pharmacokinetic data. None of the existing pharmacokinetic and toxicity databases contain either MTD or DLT. Among 268 candidate trials, four drug combinations were studied in other phase I trials before 2018; 185 combinations had complete or partial information on drug interactions or overlapping toxicity, and 79 combinations did not have available information. Two drug combination trials were selected as case studies. The nivolumab-axitinib trial could have been designed as a dose deescalating study, and the vinorelbine-trastuzumab emtansine trial could have been designed with a lower dose of either drug. Public data sources contain significant knowledge of the drug combination phase I trial design. Some important data (MTD and DLT) are not available in existing databases but in the literature. Some phase I studies could have been designed more efficiently with additional preliminary data.
Significance:
Prior preclinical and clinical knowledge is critical for designing effective and efficient cancer drug combinatory trials. We reported results on the feasibility and utility of different informatics resources for contributing to and assisting phase I trial designs based on our designed classification approach. We also found that public data sources contained significant knowledge for drug combination phase I trial design, but some critical data elements (MTD and DLT) were missing.
Data from DDR2 Coordinates EMT and Metabolic Reprogramming as a Shared Effector of FOXQ1 and SNAI1
Authors: Mitchell Allison V. , Wu Jason , Meng Fanyan , Dong Lun , Block C. James , Song Won-min , Zhang Bin , Li Jing , Wu Guojun
Published: April 2023

While multiple transcription factors (TF) have been recognized to drive epithelial–mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT-TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature. Further analysis identified DDR2 as the most upregulated receptor tyrosine kinase and a shared downstream effector of FOXQ1 and SNAI1 in triple-negative breast cancer (TNBC) cell lines. Alteration of DDR2 expression in either FOXQ1- or SNAI1-driven EMT models or in TNBC cells resulted in a profound change of cell motility without significantly impacting EMT marker expression, cell morphology, or the stem cell population. Finally, we demonstrated that knockdown of DDR2 in the FOXQ1-driven EMT model and TNBC cell line significantly altered the global metabolic profile, including glutamine-glutamate and aspartic acid recycling.
Significance:
The critical role of DDR2 in cancer metastasis has been well established. However, the exact function of DDR2 in driving cancer metastatic progression remains unclear. The results of our current study provide new insights into the cancer-driving function of DDR2, suggesting that DDR2, as a shared effector of the EMT program, may drive tumor progression by promoting breast cancer cell motility and metabolic reprogramming.
Data from Pharmacologic Inhibition of SHP2 Blocks Both PI3K and MEK Signaling in Low-epiregulin HNSCC via GAB1
Authors: Kurupi Richard , Floros Konstantinos V. , Jacob Sheeba , Chawla Ayesha T. , Cai Jinyang , Hu Bin , Puchalapalli Madhavi , Coon Colin M. , Khatri Rishabh , Crowther Giovanna Stein , Egan Regina K. , Murchie Ellen , Greninger Patricia , Dalton Krista M. , Ghotra Maninderjit S. , Boikos Sosipatros A. , Koblinski Jennifer E. , Harada Hisashi , Sun Yue , Morgan Iain M. , Basu Devraj , Dozmorov Mikhail G. , Benes Cyril H. , Faber Anthony C.
Published: April 2023

Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found head and neck squamous cell carcinoma (HNSCC) was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCCs, resulting in downregulation of mTORC signaling and antitumor effects across several HNSCC mouse models, including an human papillomavirus (HPV+) patient-derived xenograft. Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2–GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. In the presence of SHP2 inhibitor, HNSCCs are highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin.
Significance:
This work identifies a novel role of SHP2 inhibitor by dual downregulation of PI3K and MEK pathways, through loss of GAB1 activation and disruption of GAB1 complexes in low-epiregulin HNSCC.
Why Should Orchidopexy Be Performed in Congenital Hypogonadotropic Hypogonadism, and When?
Authors: Bensalah-Hammoutene Meriem , Van Vliet Guy
Published: April 2023

Background: In otherwise normal boys with undescended testes, early orchidopexy is recommended to preserve fertility, to decrease the risk of testicular cancer, and to facilitate its detection. Indeed, compared to the general population, the risk of testicular cancer is increased two- to eight-fold in isolated cryptorchidism and usually occurs before the age of 40 years. By contrast, when cryptorchidism is associated with congenital hypogonadotropic hypogonadism, the risk of testicular cancer is unknown. Objective: The aim of this study was to determine the characteristics of testicular cancer when cryptorchidism is associated with congenital hypogonadotropic hypogonadism. Methods: We conducted a PubMed research without date limits including the following key words: hypogonadism, hypogonadotropic hypogonadism, testicular cancer, testicular germ cell tumors, undescended testis, Kallmann syndrome, FSH, AFP (α foeto protein), βHCG. Results: Only 3 patients with testicular cancer and congenital hypogonadotropic hypogonadism have been published in the past 4 decades and two were diagnosed at 50 and 64 years. Conclusion: Gonadotropin deficiency may protect against testicular cancer, and orchidopexy in this context may be deferred.
O uso de agentes psicodélicos no tratamento da dependência de álcool e tabaco: revisão integrativa
Authors: Borges Eduarda Medrado Araújo , Barbosa Junior Glauber Carvalho , Araújo Alyce Maryana Costa , Moraes Marianna Nunes de , Nunes Jonatha Rospide
Published: April 2023

Objetivo: analisar os estudos que abordam o o uso de agentes psicodélicos no tratamento da dependência de álcool e tabaco no contexto nacional e internacional. Método: revisão integrativa na Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Medical Literature Analysis and Retrievel System Online (Medline), Scientific Eletronic Library Online (SciELO), EBSCO e PubMed, utilizando-se os descritores: “Alucinógenos”, “Dependência Química”, “Tratamento”, “Alcoolismo”, “Tabagismo”, “Hallucinogens”, “Chemical Dependence”, “Treatment”, “Alcoholism”, “Tobacco Use Disorder”. Resultados: a amostra final totalizou 14 artigos, que abordaram o uso de agentes psicodélicos no tratamento de dependência de álcool e tabaco, no contexto nacional e internacional. Conclusão: o uso de agentes psicodélicos no tratamento da dependência de álcool e tabaco, não é conclusivo no tratamento da dependência química como terapêutica única, entretanto, sua utilização pode ser uma inovação eficaz para os modelos atuais de tratamentos, de modo que engloba a experiência psicodélica do paciente e a relação desta com o tratamento.
Protocolo assistencial para o tratamento da lombalgia crônica: projeto piloto
Authors: Mello Grasiele Correa de , Oliveira Carla Ferro de , Postal Morgana
Published: April 2023

As doenças da coluna representam uma das maiores causas de morbidade e incapacidade laboral dentre os distúrbios que acometem o sistema musculoesquelético. As etiologias para essa queixa são variadas e podem ser de origem inflamatória, degenerativa, neoplásica, reumatológicas, posturais dentre outras , o que torna seu tratamento desafiador. Entretanto, a literatura demonstra que mais de 90% das lombalgias são de caráter inespecífico, ou seja, caracterizadas pela ausência de alterações estruturais como redução do espaço do disco, compressão de raiz nervosa, lesão óssea ou articular.