tbuckley/cabot-search huggingface dataset:
Chemotherapy Coupled to Macrophage Inhibition Induces T-cell and B-cell Infiltration and Durable Regression in Triple-Negative Breast Cancer
Authors: Swarnima Singh, Nigel Lee, Diego A. Pedroza, Igor L. Bado, Clark Hamor, Licheng Zhang, Sergio Aguirre, Jingyuan Hu, Yichao Shen, Yitian Xu, Yang Gao, Na Zhao, Shu-Hsia Chen, Ying-Wooi Wan, Zhandong Liu, Jeffrey T. Chang, Daniel Hollern, Charles M. Perou, Xiang H.F. Zhang, Jeffrey M. Rosen
Journal: Cancer Research (2022)

Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful antitumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small-molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single-cell RNA sequencing characterized tumor-infiltrating lymphocytes including Th cells and antigen-presenting B cells that were highly enriched in responders to combination therapy. In one model that exhibited long-term posttreatment tumor regression, high-dimensional imaging techniques identified the close spatial localization of B220+/CD86+-activated B cells and CD4+ T cells in tertiary lymphoid structures that were present up to 6 weeks posttreatment. The transcriptional and metabolic heterogeneity of TAMs was also characterized in two closely related claudin-low/mesenchymal subtype tumor models with differential treatment responses. A murine TAM signature derived from the T12 model was highly conserved in human claudin-low breast cancers, and high expression of the TAM signature correlated with reduced overall survival in patients with breast cancer. This TAM signature may help identify human patients with claudin-low breast cancer that will benefit from the combination of cyclophosphamide and anti-CSF1R therapy. These studies illustrate the complexity of the tumor immune microenvironment and highlight different immune responses that result from rational immunotherapy combinations.
34P RET-MAP: An international multi-center study on clinicopathologic features and treatment response in patients with NSCLC and RET fusions
Authors: A. Marinello, M. Duruisseaux, W.S. Zrafi, F.G. Dall'Olio, G. Massa, P. Iranzo, F. Tabbò, F. Guisier, C. Lindsay, V. Fallet, C. Audigier-Valette, L. Mezquita, A. Calles, G. Mountzios, M. Tagliamento, J. Raimbourg, S. Terrisse, D. Planchard, B. Besse, M. Aldea
Journal: Annals of Oncology (2022)
Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas
Authors: Shiyou Wei, Delong Yin, Shengnan Yu, Xiang Lin, Milan R. Savani, Kuang Du, Yin Ku, Di Wu, Shasha Li, Hao Liu, Meng Tian, Yaohui Chen, Michelle Bowie, Seethalakshmi Hariharan, Matthew Waitkus, Stephen T. Keir, Eric T. Sugarman, Rebecca A. Deek, Marilyne Labrie, Mustafa Khasraw, Yiling Lu, Gordon B. Mills, Meenhard Herlyn, Kongming Wu, Lunxu Liu, Zhi Wei, Keith T. Flaherty, Kalil Abdullah, Gao Zhang, David M. Ashley
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas. Experimental Design: A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line–derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib. Results: Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response. Conclusions: These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.
A Randomized Phase II Study of Nivolumab Monotherapy or Nivolumab Combined with Ipilimumab in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Arun S. Singh, J. Randolph Hecht, Lee Rosen, Zev A. Wainberg, Xiaoyan Wang, Michael Douek, Anahis Hagopian, Rachel Andes, Lauren Sauer, Sandra R. Brackert, Warren Chow, Ronald DeMatteo, Fritz Christian Eilber, John A. Glaspy, Bartosz Chmielowski
Journal: Clinical Cancer Research (2021)

Most gastrointestinal stromal tumors (GIST) are driven by KIT/PDGFRa mutations. Tyrosine kinase inhibitor benefit is progressively less after imatinib failure. This phase II trial analyzed the efficacy of nivolumab (N) or nivolumab + ipilimumab (N + I) in patients with refractory GIST.Patients with advanced/metastatic GIST refractory to at least imatinib were randomized 1:1 in a noncomparative, parallel group, unblinded phase II trial of N (240 mg every 2 weeks) or N + I (240 mg every 2 weeks + 1 mg/kg every 6 weeks). The primary endpoint was the objective response rate of N alone or N+I by RECIST 1.1 in the intent-to-treat population.A total of 36 patients with a median of 3 (1-6) prior lines of therapies were enrolled. Ten of 19 (52.6%) patients had stable disease (SD) for a clinical benefit rate (CBR) of 52.6% in the N arm and the median progression-free survival (PFS) was 11.7 weeks [95% confidence interval (CI), 7.0-17.4]. In the N+I arm, 1 of 16 (6.7%) patients had a complete response (CR) and 4/16 (25.0%) had SD for a CBR of 31.3% and a median PFS of 8.3 weeks (95% CI, 5.6-22.2). The 4- and 6-month PFS were 42.1% and 26.3%, respectively for N, and 31.3% and 18.8%, respectively for N+I. The most common adverse events (AE) attributed to N and N+I were fatigue: 13.9% and 22.2%, respectively. There were nine total attributable grade 3-4 AEs.The primary endpoint of response rate > 15% was not observed for N or N + I. In a heavily pretreated GIST population, responses and long-term disease control with both N and N+I were observed. No new safety signals have been observed.
Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma
Authors: Katsuyoshi Takata, Lauren C. Chong, Daisuke Ennishi, Tomohiro Aoki, Michael Yu Li, Avinash Thakur, Shannon Healy, Elena Viganò, Tao Dao, Daniel Kwon, Gerben Duns, Julie S. Nielsen, Susana Ben-Neriah, Ethan Tse, Stacy S. Hung, Merrill Boyle, Sung Soo Mun, Christopher M. Bourne, Bruce Woolcock, Adèle Telenius, Makoto Kishida, Shinya Rai, Allen W. Zhang, Ali Bashashati, Saeed Saberi, Gianluca D’Antonio, Brad H. Nelson, Sohrab P. Shah, Pamela A. Hoodless, Ari M. Melnick, Randy D. Gascoyne, Joseph M. Connors, David A. Scheinberg, Wendy Béguelin, David W. Scott, Christian Steidl
Journal: Journal of Clinical Investigation (2022)

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.
Effect of alglucosidase alfa dosage on survival and walking ability in patients with classic infantile Pompe disease: a multicentre observational cohort study from the European Pompe Consortium
Authors: Imke Anne Maartje Ditters, Hidde Harmen Huidekoper, Michelle Elisabeth Kruijshaar, Dimitris Rizopoulos, Andreas Hahn, Tiziana Enrica Mongini, François Labarthe, Marine Tardieu, Brigitte Chabrol, Anais Brassier, Rossella Parini, Giancarlo Parenti, Nadine Anna Maria Elisabeth van der Beek, Ans Tjitske van der Ploeg, Johanna Maria Pieternel van den Hout, Eugen Mengel, Julia Hennermann, Martin Smitka, Nicole Muschol, Thorsten Marquardt, Martina Marquardt, Charlotte Thiels, Marco Spada, Veronica Pagliardini, Francesca Menni, Roberto della Casa, Federica Deodato, Serena Gasperini, Alberto Burlina, Alice Donati, Samia Pichard, François Feillet, Fréderic Huet, Karine Mention, Didier Eyer, Alice Kuster, Caroline Espil Taris, Jérémie Lefranc, Magalie Barth, Henri Bruel, Laurent Chevret, Gaele Pitelet, Catherine Pitelet, François Rivier, Dries Dobbelaere
Journal: The Lancet Child & Adolescent Health (2021)
Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis
Authors: Yi-ting Wei, Xu-ru Wang, Chunguang Yan, Fang Huang, Yunpeng Zhang, Xueming Liu, Zhi-fa Wen, Xiao-tong Sun, Yue Zhang, Yong-qiang Chen, Rong Gao, Ning Pan, Li-xin Wang
Journal: Cancer Research (2022)

Abstract The immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5′-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer. Significance: Thymosin α-1 improves the curative effect of chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis.
68Ga-PSMA PET/CT Scan Leading to Diagnosis of PSMA-Positive Rectal Adenocarcinoma in a Patient With Prostate Cancer
Authors: Ghazal Norouzi, Alireza Rezaei, Zohreh Adinehpour, Hamidreza Amini, Reza Vali
Journal: Clinical Nuclear Medicine (2022)

Abstract A 59-year-old prostate cancer patient, status post radical prostatectomy, was referred to our department for restaging with 68 Ga–prostate-specific membrane antigen (PSMA) PET/CT scan. Aside multiple metastatic lesions involving pelvic lymph nodes as well as the right femoral trochanter, a PSMA-positive rectal wall thickening was detected. Colonoscopy correlation and tissue diagnosis, recommended to rule out accompanying primary malignancy, confirmed the presence of rectal adenocarcinoma. This case signifies the importance of requesting pathological correlation for unexplained PSMA-positive lesions, emphasizing the potential role PSMA ligands may play in detecting occult second primary malignancies, especially synchronous/metachronous colorectal cancers.
Concerns over functional experiments, interpretation, and required controls
Authors: Eddie C.Y. Wang, Ceri A. Fielding, Richard J. Stanton
Journal: Journal of Clinical Investigation (2022)

To the Editor: Hsieh et al. (1) provide comprehensive data correlating NK phenotypes with SARS-CoV-2 clearance.However, the functional experiments provided to support their mechanistic conclusions are far from definitive and are missing the correct comparators required for appropriate interpretation.In Figure 3 and Supplemental Figure 5, the authors claim that CD155 and nectin-4 are upregulated by SARS-CoV-2.Nucleocapsid expression in partially infected cultures was used to differentiate infected from uninfected cells, yet uninfected cells in this system respond to interferons and cytokines released by infected cells (2); CD155 and nectin-4 levels must be compared to levels in mock-infected cells.Furthermore, the magnitude of the changes is small.Without showing absolute changes (e.g., flow cytometry plots), it is impossible to determine whether effects are biologically meaningful.Interpretation of immunofluorescence staining of infected lung tissue is also problematic.End-stage COVID patients have severe inflammation, which upregulates CD155.Demonstrating that this effect is specific to live cells productively infected with SARS-CoV-2 requires a much more robust quantitative comparison of uninfected and infected cells.Additionally, viruses frequently retain NK ligands intracellularly (3-5); thus, the presented histological staining is inappropriate, as it cannot differentiate intracellular from cell-surface staining.The authors use spike pseudotyped lentivirus to claim that SARS-CoV-2 upregulates CD155, resulting in decreased NK killing in animal models.However, pseudovirus is only appropriate to […]
IMMUNOTHERAPY
Authors: Hermann Einsele
Journal: HemaSphere (2022)

Cellular Immunotherapy involving CAR T cells, TCR transduced T cells and T cell engaging antibodies are increasingly used for the treatment of multiple myeloma. Currently, only one, maybe two CAR T cell products are approved for clinical use in patients with relapsed / refractory multiple myeloma (for the 3 lines of prior therapy and progression under the last treatment). One bispecific antibody, which is also targeting BCMA on myeloma cells, will soon be approved for clinical use in heavily pre-treated patients with multiple myeloma. Due to the fact that T cell fitness and repopulation potential of T cells is clearly increased in earlier lines of therapy, there are increasing studies now testing CAR T cells and bispecific antibodies in earlier lines of treatment of multiple myeloma. We need additional studies in early relapse frontline therapy with CAR T cells and bispecific antibodies to optimize their anti-myeloma potential and on the other hand future trials will have to study whether the higher T cell fitness and longer persistence of CAR T cell might also increase toxicity of CAR T cells and/or bispecific antibodies when used in frontline therapy or for early relapse. We also have to screen whether the hematotoxicity, which is a significant side effect, of CAR T cell therapy and T cell engaging antibodies will be reduced if the patient is less heavily pre-treated. So in summary, we urgently need more trials with T cell engaging antibodies, CAR T cells and also TCR transduced T cells in earlier lines of therapy, including randomized trials comparing CAR T cells and bispecific antibodies to high dose chemotherapy and autologous stem cells transplantation and thus to further define the role of the novel immunotherapies in early lines of therapy for multiple myeloma.
Immunotherapy in Pancreatic Adenocarcinoma: Beyond “Copy/Paste”
Authors: Robert Hester, Pawel K. Mazur, Florencia McAllister
Journal: Clinical Cancer Research (2021)

Immunotherapy has dramatically changed the cancer treatment landscape during the past decade, but very limited efficacy has been reported against pancreatic cancer. Several factors unique to pancreatic cancer may explain the resistance: the well-recognized suppressive elements in the tumor microenvironment, the functional and structural barrier imposed by the stroma components, T-cell exhaustion, the choice of perhaps the wrong immune targets, and microbial factors including gut dysbiosis and the unexpected presence of tumor microbes. Furthermore, we discuss various strategies to overcome these barriers.
Abstract MP65: Prospective Association Between Adiponectin Levels With Neurocognitive And Neuroimaging Outcomes: Findings From The Dallas Heart Study
Authors: Omar Shaikh, Elaine Wu, Joseph Maldjian, Fang Yu, Zabecca Brinson, Christian Lopez, Heidi Rosetti, Munro Cullum, Philipp E Scherer, Jarett D Berry
Journal: Circulation (2022)

Introduction: Adiponectin’s association with neurocognitive outcomes has been inconsistent. Therefore, we sought to characterize the association between adiponectin and subclinical markers of both neurocognitive impairment and neuroimaging phenotypes. Methods: We included 1,199 participants (mean age of 43.4 , 62.6 % non-white, 56.5 % female) from the Dallas Heart Study, a longitudinal, multiethnic cohort study. Adiponectin was measured at exam 1 (2000-2002) and both Montreal Cognitive Assessment (MoCA) test scores and brain MRI (3T, Philips) were measured at exam 2 (2007-2009) providing measures of total brain volume, hippocampal volume, and white matter hyperintensity volume (WMH). Baseline characteristics were compared across race- and sex-specific quintiles of adiponectin. The association between adiponectin, MoCA, and brain MRI outcomes were evaluated using regression models adjusted for age, race, sex, education, body mass index, systolic blood pressure, fasting glucose, and abdominal fat. Results: Adiponectin levels were higher in women (8.9 μg/mL) than men (6.37 μg/mL ) and in whites (9.15 μg/mL) than non-whites (6.99 μg/mL). Higher levels of adiponectin were associated with more favorable metabolic profiles. Although there was no association between adiponectin and the reported outcomes when analyzed as a continuous variable (per SD), we observed a consistent, non-linear association between adiponectin and MoCA (Table 1) and brain volume (Table 1) and hippocampal volume (Table 1), with the highest MoCA score and brain volume measure in quintile 3 (vs. quintile 1). In contrast, we observed no consistent association between adiponectin and WMH when adiponectin was analyzed as a continuous (per SD) or as an ordinal variable. Conclusion: We observed a non-linear association between adiponectin and both MoCA scores and brain volumes in a cohort of middle-aged adults. Further research is needed to understand how intermediate values of adiponectin might promote more favorable neurocognitive outcomes.
Authors’ Reply: Advanced Tertiary Lymphoid Tissues in Protocol Biopsies in Kidney Transplant Recipients: Addressing Additional Methods To Detect Intragraft B Cells
Authors: Yuki Sato, Yu Ho Lee, Keisuke Taniguchi, Takahisa Yoshikawa, Peter Boor, Jürgen Floege, Motoko Yanagita
Journal: Journal of the American Society of Nephrology (2022)

In our manuscript[1][1] "Advanced tertiary lymphoid tissues in protocol biopsies are associated with progressive graft dysfunction on kidney transplant recipients," we demonstrated that developmentally mature advanced tertiary lymphoid tissues (stage II TLTs), ectopic lymphoid tissues formed in
Increased 68Ga-FAPI Uptake of Symptomatic Intracranial Atherosclerotic Plaque Revealed by PET/MR
Authors: Qiao Yang, Zongmuyu Zhang, Mingli Li, Wei-Hai Xu, Li Huo
Journal: Clinical Nuclear Medicine (2022)

Abstract A 58-year-old man was enrolled in our 68 Ga-FAPI PET/MR study for evaluation of stroke etiology. He had left thalamus and cerebellum infarction 6 months ago, and left occipital lobe infarction 2 years ago. 68 Ga-FAPI PET/MR showed focal uptake along the low segment of the basilar artery. We hypothesize that the FAPI-avid plaque of basilar artery may account for the embolic events resulting in downstream infarction. Thus FAP-targeted imaging may have a potential for detection of vulnerable plaques.
Cardiac Resident Macrophages Prevent Fibrosis and Stimulate Angiogenesis
Authors: Xavier S. Revelo, Preethy Parthiban, Chen Chen, Fanta Barrow, Gavin Fredrickson, Haiguang Wang, Doğacan Yücel, Adam Herman, Jop H. van Berlo
Journal: Circulation Research (2021)

The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads to heart failure. Recently, a role for recruited macrophages in determining the transition from compensated to decompensated hypertrophy has been established. However, whether cardiac resident immune cells influence the early phase of hypertrophy development has not been established.To assess the role of cardiac immune cells in the early hypertrophy response to cardiac pressure overload induced by transverse aortic constriction (TAC).We performed cytometry by time-of-flight to determine the identity and abundance of immune cells in the heart at 1 and 4 weeks after TAC. We observed a substantial increase in cardiac macrophages 1 week after TAC. We then conducted Cite-Seq single-cell RNA sequencing of cardiac immune cells isolated from 4 sham and 6 TAC hearts. We identified 12 clusters of monocytes and macrophages, categorized as either resident or recruited macrophages, that showed remarkable changes in their abundance between sham and TAC conditions. To determine the role of cardiac resident macrophages early in the response to a hypertrophic stimulus, we used a blocking antibody against macrophage colony-stimulating factor 1 receptor (CD115). As blocking CD115 initially depletes all macrophages, we allowed the replenishment of recruited macrophages by monocytes before performing TAC. This preferential depletion of resident macrophages resulted in enhanced fibrosis and a blunted angiogenesis response to TAC. Macrophage depletion in CCR2 (C-C chemokine receptor type 2) knockout mice showed that aggravated fibrosis was primarily caused by the recruitment of monocyte-derived macrophages. Finally, 6 weeks after TAC these early events lead to depressed cardiac function and enhanced fibrosis, despite complete restoration of cardiac immune cells.Cardiac resident macrophages are a heterogeneous population of immune cells with key roles in stimulating angiogenesis and inhibiting fibrosis in response to cardiac pressure overload.