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including anti-PD-1 immune checkpoint blocking (ICB) antibodies, have revolutionized the treatment of many solid malignancies. However, their efficacy in breast cancer has been limited to a subset of patients with triple-negative breast cancer, where ICBs are routinely combined with a range of cytotoxic and targeted agents. Reliable biomarkers predictive of the therapeutic response to ICB in breast cancer are critically missing, though a combination response has been associated with immunogenic cell death (ICD). Here, we utilized a recently developed integrated analytical platform, the multiplex implantable microdevice assay (MIMA), to evaluate the presence and spatial cell relations of literature-based candidate markers predictive of ICB efficacy in luminal mouse mammary carcinoma. MIMA integrates (i) an implantable microdevice for the localized delivery of small amounts of drugs inside the tumor bed with (ii) sequential multiplex immunohistochemistry (mIHC) and spatial cell analysis pipelines to rapidly (within days) describe drug mechanisms of action and find predictive biomarkers in complex tumor tissue. We show that the expression of cleaved caspase-3, ICAM-1, neuropilin-1, myeloperoxidase, calreticulin, galectin-3, and PD-L1 were spatially associated with the efficacy of panobinostat, a pan-HDAC inhibitor that was previously shown to induce immunogenic cell death and synergize with anti-PD-1 in breast cancer. PD-L1 by itself, however, was not a reliable predictor. Instead, ICB efficacy was robustly identified through the in situ hotspot detection of galectin-3-positive non-proliferating tumor zones enriched in cell death and infiltrated by anti-tumor cytotoxic neutrophils positive for ICAM-1 and neuropilin-1. Such hotspots can be specifically detected using distance-based cluster analyses. Single-cell measurements of the functional states in the tumor microenvironment suggest that both qualitative and quantitative effects might drive effective therapy responses. Overall, the presented study provides (i) complementary biological knowledge about the earliest cell events of induced anti-tumor immunity in breast cancer, including the emergence of resistant cancer stem cells, and (ii) newly identified biomarkers in form of specific spatial cell associations. The approach used standard cell-type-, IHC-, and FFPE-based techniques, and therefore the identified spatial clustering of in situ biomarkers can be readily integrated into existing clinical or research workflows, including in luminal breast cancer. Since early drug responses were detected, the biomarkers could be especially applicable to window-of-opportunity clinical trials to rapidly discriminate between responding and resistant patients, thus limiting unnecessary treatment-associated toxicities.<\/jats:p>","DOI":"10.3390\/cells12020308","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T05:09:32Z","timestamp":1673586572000},"page":"308","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Panobinostat Induced Spatial In Situ Biomarkers Predictive of Anti-PD-1 Efficacy in Mouse Mammary Carcinoma"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3128-7214","authenticated-orcid":false,"given":"Zuzana","family":"Tatarova","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, OR 97239, USA"},{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA"},{"name":"Department of Radiology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan C.","family":"Blumberg","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AeSoon","family":"Bensen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, OR 97239, USA"},{"name":"Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon B.","family":"Mills","sequence":"additional","affiliation":[{"name":"Division of Oncologic Sciences, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2512-2007","authenticated-orcid":false,"given":"Oliver","family":"Jonas","sequence":"additional","affiliation":[{"name":"Department of Radiology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1038\/s41587-022-01379-y","article-title":"A Multiplex Implantable Microdevice Assay Identifies Synergistic Combinations of Cancer Immunotherapies and Conventional Drugs","volume":"40","author":"Tatarova","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41571-018-0142-8","article-title":"Cancer Immunoediting and Resistance to T Cell-Based Immunotherapy","volume":"16","author":"Teng","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.semcancer.2021.03.002","article-title":"Therapeutic Applications of the Cancer Immunoediting Hypothesis","volume":"78","author":"Desai","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1016\/j.cell.2018.11.006","article-title":"Putting the Immunologic Brakes on Cancer","volume":"175","author":"Wolchok","year":"2018","journal-title":"Cell"},{"key":"ref_5","first-page":"922","article-title":"Immunotherapy for the Treatment of Breast Cancer: Checkpoint Blockade, Cancer Vaccines, and Future Directions in Combination Immunotherapy","volume":"14","author":"McArthur","year":"2016","journal-title":"Clin. Adv. Hematol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eaat7807","DOI":"10.1126\/scitranslmed.aat7807","article-title":"The Hallmarks of Successful Anticancer Immunotherapy","volume":"10","author":"Galluzzi","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_7","first-page":"150","article-title":"The Tale of TILs in Breast Cancer: A Report from The International Immuno-Oncology Biomarker Working Group","volume":"7","author":"Haynes","year":"2021","journal-title":"Nat. Partn. J. Breast Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S1470-2045(17)30904-X","article-title":"Tumour-Infiltrating Lymphocytes and Prognosis in Different Subtypes of Breast Cancer: A Pooled Analysis of 3771 Patients Treated with Neoadjuvant Therapy","volume":"19","author":"Denkert","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Marra, A., Viale, G., and Curigliano, G. (2019). Recent Advances in Triple Negative Breast Cancer: The Immunotherapy Era. BMC Med., 17.","DOI":"10.1186\/s12916-019-1326-5"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1056\/NEJMoa1809615","article-title":"Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer","volume":"379","author":"Schmid","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_11","first-page":"123","article-title":"De-Glycosylated Membrane PD-L1 in Tumor Tissues as a Biomarker for Responsiveness to Atezolizumab (Tecentriq) in Advanced Breast Cancer Patients","volume":"12","author":"Li","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.immuni.2013.03.003","article-title":"Anticancer Chemotherapy-Induced Intratumoral Recruitment and Differentiation of Antigen-Presenting Cells","volume":"38","author":"Ma","year":"2013","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1084\/jem.20050915","article-title":"Caspase-Dependent Immunogenicity of Doxorubicin-Induced Tumor Cell Death","volume":"202","author":"Casares","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1172\/JCI94586","article-title":"Dinaciclib Induces Immunogenic Cell Death and Enhances Anti- PD1\u2013Mediated Tumor Suppression","volume":"128","author":"Javaid","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1523097","DOI":"10.1080\/2162402X.2018.1523097","article-title":"Priming Anti-Tumor Immunity by Radiotherapy: Dying Tumor Cell-Derived DAMPs Trigger Endothelial Cell Activation and Recruitment of Myeloid Cells","volume":"8","author":"Krombach","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"450","DOI":"10.4049\/jimmunol.1701021","article-title":"Critical Interactions between Immunogenic Cancer Cell Death, Oncolytic Viruses, and the Immune System Define the Rational Design of Combination Immunotherapies","volume":"200","author":"Workenhe","year":"2018","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.1021\/acsnano.1c09048","article-title":"Nitric Oxide Induces Immunogenic Cell Death and Potentiates Cancer Immunotherapy","volume":"16","author":"Jiang","year":"2022","journal-title":"ACS Nano"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e955691","DOI":"10.4161\/21624011.2014.955691","article-title":"Consensus Guidelines for the Detection of Immunogenic Cell Death","volume":"3","author":"Kepp","year":"2014","journal-title":"Oncoimmunology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1158\/2159-8274.CD-10-0028","article-title":"Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy","volume":"1","author":"Denardo","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41590-022-01132-2","article-title":"Immunogenic Cell Stress and Death","volume":"23","author":"Kroemer","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/nm1523","article-title":"Calreticulin Exposure Dictates the Immunogenicity of Cancer Cell Death","volume":"13","author":"Obeid","year":"2007","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/s41418-021-00853-5","article-title":"Stress-Induced Inflammation Evoked by Immunogenic Cell Death Is Blunted by the IRE1\u03b1 Kinase Inhibitor KIRA6 through HSP60 Targeting","volume":"29","author":"Rufo","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-immunol-032712-100008","article-title":"Immunogenic Cell Death in Cancer Therapy","volume":"31","author":"Kroemer","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/cdd.2017.15","article-title":"Pathogen Response-like Recruitment and Activation of Neutrophils by Sterile Immunogenic Dying Cells Drives Neutrophil-Mediated Residual Cell Killing","volume":"24","author":"Garg","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1386829","DOI":"10.1080\/2162402X.2017.1386829","article-title":"Trial Watch: Immunogenic Cell Death Induction by Anticancer Chemotherapeutics","volume":"6","author":"Garg","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"892813","DOI":"10.3389\/fonc.2022.892813","article-title":"Association of Cell Death Markers with Tumor Immune Cell Infiltrates After Chemo-Radiation in Cervical Cancer","volume":"12","author":"Oltean","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chang, Y.H., Tsujikawa, T., Margolin, A., Coussens, L.M., and Gray, J.W. (2017, January 11\u201315). Multiplexed Immunohistochemistry Image Analysis Using Sparse Coding. Proceedings of the 2017 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Jeju, Korea.","DOI":"10.1109\/EMBC.2017.8037744"},{"key":"ref_28","unstructured":"Thurin, M., Cesano, A., and Marincola, F.M. (2020). Cyclic Multiplexed-Immunofluorescence (CmIF), a Highly Multiplexed Method for Single-Cell Analysis. Biomarkers for Immunotherapy of Cancer: Methods and Protocols, Springer."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41698-021-00165-4","article-title":"Characterizing Advanced Breast Cancer Heterogeneity and Treatment Resistance through Serial Biopsies and Comprehensive Analytics","volume":"5","author":"Li","year":"2021","journal-title":"NPJ Precis. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/s41586-019-1876-x","article-title":"The Single-Cell Pathology Landscape of Breast Cancer","volume":"578","author":"Jackson","year":"2020","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"284ra57","DOI":"10.1126\/scitranslmed.3010564","article-title":"An Implantable Microdevice to Perform High-Throughput in Vivo Drug Sensitivity Testing in Tumors","volume":"7","author":"Jonas","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 Years of Image Analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1746-1596-2-8","article-title":"Quantitative Image Analysis of Immunohistochemical Stains Using a CMYK Color Model","volume":"2","author":"Pham","year":"2007","journal-title":"Diagn. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.mie.2019.05.039","article-title":"Chapter One\u2014High-dimensional multiplexed immunohistochemical characterization of immune contexture in human cancers","volume":"635","author":"Banik","year":"2020","journal-title":"Methods Enzymol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"R100","DOI":"10.1186\/gb-2006-7-10-r100","article-title":"CellProfiler: Image Analysis Software for Identifying and Quantifying Cell Phenotypes","volume":"7","author":"Carpenter","year":"2006","journal-title":"Genome Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"413","DOI":"10.21037\/tlcr.2019.08.09","article-title":"The Association of PD-L1 Expression with the Efficacy of Anti-PD-1\/PD-L1 Immunotherapy and Survival of Non-Small Cell Lung Cancer Patients: A Meta-Analysis of Randomized Controlled Trials","volume":"8","author":"Xu","year":"2019","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: The Universal Protein Knowledgebase in 2021","volume":"49","author":"Bateman","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1158\/2159-8290.CD-16-0778","article-title":"Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity","volume":"7","author":"Patnaik","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/0959-8049(95)00551-X","article-title":"Expression of MHC Molecules and ICAM-1 on Non-Small Cell Lung Carcinomas: Association with Early Lymphatic Spread of Tumour Cells","volume":"32","author":"Passlick","year":"1996","journal-title":"Eur. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/nm.4466","article-title":"High-Dimensional Single-Cell Analysis Predicts Response to Anti-PD-1 Immunotherapy","volume":"24","author":"Krieg","year":"2018","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.ccell.2018.03.008","article-title":"The Immune Revolution: A Case for Priming, Not Checkpoint","volume":"33","author":"Vonderheide","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/30845","article-title":"Licence to Kill","volume":"393","author":"Lanzavecchla","year":"1998","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of Tumor-Associated Neutrophil Phenotype by TGF-\u03b2: \u201cN1\u201d versus \u201cN2\u201d TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1232221","DOI":"10.1080\/2162402X.2016.1232221","article-title":"Tumor-Associated Neutrophils Display a Distinct N1 Profile Following TGF\u03b2 Modulation: A Transcriptomics Analysis of pro- vs. Antitumor TANs","volume":"5","author":"Shaul","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.it.2012.08.002","article-title":"Calreticulin in the Immune System: Ins and Outs","volume":"34","author":"Raghavan","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature21409","article-title":"Class IIa HDAC Inhibition Reduces Breast Tumours and Metastases through Anti-Tumour Macrophages","volume":"543","author":"Guerriero","year":"2017","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.devcel.2016.08.003","article-title":"TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-Direct Autophagy in Endomembrane Damage Homeostasis","volume":"39","author":"Chauhan","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1126\/science.1208347","article-title":"Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice","volume":"334","author":"Michaud","year":"2011","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1023\/B:GLYC.0000014089.17121.cc","article-title":"Seeing Strangers or Announcing \u201cDanger\u201d: Galectin-3 in Two Models of Innate Immunity","volume":"19","author":"Sato","year":"2002","journal-title":"Glycoconj. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.1182\/blood.V91.9.3430","article-title":"Galectin-3 Activates the NADPH-Oxidase in Exudated but Not Peripheral Blood Neutrophils","volume":"91","author":"Karlsson","year":"2018","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1182\/blood-2004-12-4942","article-title":"ICAM-1 Regulates Neutrophil Adhesion and Transcellular Migration of TNF-\u03b1-Activated Vascular Endothelium under Flow","volume":"106","author":"Yang","year":"2005","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4458","DOI":"10.4049\/jimmunol.1600709","article-title":"Galectin-3: A Positive Regulator of Leukocyte Recruitment in the Inflamed Microcirculation","volume":"198","author":"Gittens","year":"2018","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10295","DOI":"10.1074\/jbc.M116.773051","article-title":"Neuropilin-1 Mediates Neutrophil Elastase Uptake and Cross-Presentation in Breast Cancer Cells","volume":"292","author":"Kerros","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/ni789","article-title":"A Neuronal Receptor, Neuropilin-I, Is Essential for the Initiation of the Primary Immune Response","volume":"3","author":"Tordjman","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/s41388-020-01560-0","article-title":"Insights from Transgenic Mouse Models of PyMT-Induced Breast Cancer: Recapitulating Human Breast Cancer Progression in Vivo","volume":"40","author":"Attalla","year":"2021","journal-title":"Oncogene"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1016\/S0002-9440(10)63568-7","article-title":"Progression to Malignancy in the Polyoma Middle T Oncoprotein Mouse Breast Cancer Model Provides a Reliable Model for Human Diseases","volume":"163","author":"Lin","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_57","first-page":"954","article-title":"Induction of Mammary Tumors by Expression of Polyomavirus Middle T Oncogene: A Transgenic Mouse Model for Metastatic Disease","volume":"12","author":"Guy","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"R76","DOI":"10.1186\/gb-2007-8-5-r76","article-title":"Identification of Conserved Gene Expression Features between Murine Mammary Carcinoma Models and Human Breast Tumors","volume":"8","author":"Herschkowitz","year":"2007","journal-title":"Genome Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/j.cell.2016.01.049","article-title":"The Basis of Oncoimmunology","volume":"164","author":"Palucka","year":"2016","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.cell.2012.02.008","article-title":"Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State","volume":"148","author":"Guo","year":"2012","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev-immunol-030409-101311","article-title":"The Sterile Inflammatory Response","volume":"28","author":"Rock","year":"2010","journal-title":"Annu. Rev. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc.2016.36","article-title":"Mechanism-Driven Biomarkers to Guide Immune Checkpoint Blockade in Cancer Therapy","volume":"16","author":"Topalian","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41379-021-00932-5","article-title":"Biomarkers of Response to Checkpoint Inhibitors beyond PD-L1 in Lung Cancer","volume":"35","author":"Sholl","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1200\/JCO.19.00739","article-title":"Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results from the Phase I\/II CheckMate 358 Trial","volume":"37","author":"Hollebecque","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1038\/s41388-020-01611-6","article-title":"Is PD-L1 a Consistent Biomarker for Anti-PD-1 Therapy? The Model of Balstilimab in a Virally-Driven Tumor","volume":"40","author":"Grossman","year":"2021","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3638","DOI":"10.1200\/JCO.19.03205","article-title":"Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer","volume":"38","author":"Mlecnik","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.cell.2017.05.005","article-title":"Interferon-\u03b3 Drives TregFragility to Promote Anti-Tumor Immunity","volume":"169","author":"Chikina","year":"2017","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"10","DOI":"10.18632\/oncotarget.11060","article-title":"Novel Regulatory Role of Neuropilin-1 in Endothelial-to-Mesenchymal Transition and Fibrosis in Pancreatic Ductal Adenocarcinoma","volume":"7","author":"Matkar","year":"2016","journal-title":"Oncotarget"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1073\/pnas.1424907112","article-title":"Macrophages Eat Cancer Cells Using Their Own Calreticulin as a Guide: Roles of TLR and Btk","volume":"112","author":"Feng","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1593\/tlo.12271","article-title":"Endoplasmic Reticulum Stress Plays a Pivotal Role in Cell Death Mediated by the Pan-Deacetylase Inhibitor Panobinostat in Human Hepatocellular Cancer Cells","volume":"6","author":"Montalbano","year":"2013","journal-title":"Transl. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1038\/s41598-017-01964-1","article-title":"A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC","volume":"7","author":"Samaraweera","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/308\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:05:17Z","timestamp":1760119517000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/308"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,13]]},"references-count":72,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12020308"],"URL":"https:\/\/doi.org\/10.3390\/cells12020308","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,13]]}}}