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In the era of evolving cancer immunotherapy, whether CAM-Ls might have a potential role as predictive biomarkers of response has been unexplored. We evaluated whether a serial blood evaluation of CTC to CAM-L ratio might predict response to immune checkpoint inhibitors in a cohort of non-small-cell lung cancer patients. At baseline, CTCs, CAM-Ls, and the CTC\/CAM-L ratio significantly correlate with both progression-free survival (PFS) and overall survival (OS). The baseline CTC\/CAM-L ratio was significantly different in early progressors (4.28 \u00b1 3.21) compared to long responders (0.42 \u00b1 0.47) (p = 0.001). In patients treated with immune checkpoint inhibitors, a CTC\/CAM-L ratio \u2264 0.25 at baseline is associated with better PFS and OS. A baseline CTC\/CAM-L ratio \u2264 0.25 is statistically significant to discriminate early progressions from durable response. The results of the present pilot study suggest that CAM-Ls together with CTCs could play an important role in evaluating patients treated with cancer immunotherapy.<\/jats:p>","DOI":"10.3390\/ijms25073752","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T12:22:46Z","timestamp":1711628566000},"page":"3752","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Circulating Cancer-Associated Macrophage-like Cells as a Blood-Based Biomarker of Response to Immune Checkpoint Inhibitors"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-2904","authenticated-orcid":false,"given":"Valentina","family":"Magri","sequence":"first","affiliation":[{"name":"Department of Pathology, Oncology and Radiology, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"De Renzi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7380-6222","authenticated-orcid":false,"given":"Luca","family":"Marino","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering, Sapienza University of Rome, 00184 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3024-2233","authenticated-orcid":false,"given":"Michela","family":"De Meo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0489-1790","authenticated-orcid":false,"given":"Marco","family":"Siringo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Oncology and Radiology, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Gelibter","sequence":"additional","affiliation":[{"name":"Department of Pathology, Oncology and Radiology, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Gareri","sequence":"additional","affiliation":[{"name":"UOC di Oncologia Medica, Ospedale Leopoldo Parodi Delfino, 00034 Colleferro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9938-6403","authenticated-orcid":false,"given":"Chiara","family":"Cataldi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Oncology and Radiology, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0299-4056","authenticated-orcid":false,"given":"Giuseppe","family":"Giannini","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Santini","sequence":"additional","affiliation":[{"name":"Department of Pathology, Oncology and Radiology, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2551-8979","authenticated-orcid":false,"given":"Chiara","family":"Nicolazzo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-2273","authenticated-orcid":false,"given":"Paola","family":"Gazzaniga","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102614","DOI":"10.1016\/j.ctrv.2023.102614","article-title":"Novel targets for immune-checkpoint inhibition in cancer","volume":"120","author":"Borgeaud","year":"2023","journal-title":"Cancer Treat. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1191681","DOI":"10.3389\/fonc.2023.1191681","article-title":"PD-1\/PD-L1 inhibitor treatment and its impact on clinical imaging in non-small cell lung cancer: A systematic review and meta-analysis of immune-related adverse events","volume":"13","author":"Mohammed","year":"2023","journal-title":"Front. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ratajczak, K., Grel, H., Olejnik, P., Jakiela, S., and Stobiecka, M. (2023). Biosensors and Bioelectronics Current progress, strategy, and prospects of PD-1\/PDL-1 immune checkpoint biosensing platforms for cancer diagnostics, therapy monitoring, and drug screening. Biosens. Bioelectron., 240.","DOI":"10.1016\/j.bios.2023.115644"},{"key":"ref_4","first-page":"e387","article-title":"Progresses in biomarkers for cancer immunotherapy","volume":"4","author":"Lin","year":"2023","journal-title":"Med. Comm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1001\/jamainternmed.2023.3603","article-title":"Assessing the Clinical Utility of Liquid Biopsies Across 5 Potential Indications from Therapy Selection to Population Screening: A Review","volume":"183","author":"Welch","year":"2023","journal-title":"JAMA Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Dao, J., Conway, P.J., Subramani, B., Meyyappan, D., Russell, S., and Mahadevan, D. (2023). Using cfDNA and ctDNA as Oncologic Markers: A Path to Clinical Validation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713219"},{"key":"ref_7","first-page":"e42731","article-title":"Advancements and Applications of Liquid Biopsies in Oncology: A Narrative Review","volume":"15","author":"Noor","year":"2023","journal-title":"Cureus"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1158\/2159-8290.CD-20-1311","article-title":"Liquid Biopsy: From Discovery to Clinical Application","volume":"11","author":"Pantel","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Xiao, J., Pohlmann, P.R., Isaacs, C., Weinberg, B.A., He, A.R., Schlegel, R., and Agarwal, S. (2021). Circulating Tumor Cells: Technologies and Their Clinical Potential in Cancer Metastasis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091111"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ejca.2019.04.019","article-title":"ScienceDirect EPAC-lung: Pooled analysis of circulating tumour cells in advanced non-small cell lung cancer","volume":"117","author":"Lindsay","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.molonc.2015.12.002","article-title":"ScienceDirect Challenges in circulating tumor cell detection by the CellSearch system 5","volume":"10","author":"Andree","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_12","first-page":"619","article-title":"Clinical utility of circulating tumor cell counting through CellSearch\u00ae: The dilemma of a concept suspended in Limbo","volume":"7","author":"Raimondi","year":"2014","journal-title":"OncoTarget Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"de Wit, S., Zeune, L.L., Hiltermann, J.T.N., Groen, H.J.M., and Dalum GVan Terstappen, L.W.M.M. (2018). Classification of Cells in CTC-Enriched Samples by Advanced Image Analysis. Cancers, 10.","DOI":"10.3390\/cancers10100377"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/s41391-020-00304-1","article-title":"Automated enumeration and phenotypic characterization of CTCs and tdEVs in patients with metastatic castration resistant prostate cancer","volume":"24","author":"Oeyen","year":"2021","journal-title":"Prostate Cancer Prostat. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.semcancer.2019.10.008","article-title":"Seminars in Cancer Biology The curious phenomenon of dual-positive circulating cells: Longtime overlooked tumor cells","volume":"60","author":"Reduzzi","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_16","first-page":"380","article-title":"Hybrid\/Atypical Forms of Circulating Tumor Cells: Current State of the Art","volume":"87","author":"Kaigorodova","year":"2022","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sutton, T.L., Patel, R.K., Anderson, A.N., Bowden, S.G., Whalen, R., Giske, N.R., and Wong, M.H. (2022). Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer. Cancers, 14.","DOI":"10.3390\/cancers14163871"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nitschke, C., Markmann, B., Konczalla, L., Kropidlowski, J., Pereira-Veiga, T., Scognamiglio, P., Sch\u00f6nrock, M., Sinn, M., T\u00f6lle, M., and Izbicki, J. (2022). Circulating Cancer Associated Macrophage-like Cells as a Potential New Prognostic Marker in Pancreatic Ductal Adenocarcinoma. Biomedicines, 10.","DOI":"10.3390\/biomedicines10112955"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1073\/pnas.1320198111","article-title":"Circulating giant macrophages as a potential biomarker of solid tumors","volume":"111","author":"Adams","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Dotse, E., Lim, K.H., Wang, M., and Wijanarko, K.J. (2022). An Immunological Perspective of Circulating Tumor Cells as Diagnostic Biomarkers and Therapeutic Targets. Life, 12.","DOI":"10.3390\/life12020323"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12943-019-0976-4","article-title":"Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell- mediated colorectal cancer metastasis","volume":"18","author":"Wei","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Huang, J., Wang, K., Xu, J., Huang, J., and Zhang, T. (2013). Prognostic Significance of Circulating Tumor Cells in Non-Small-Cell Lung Cancer Patients: A Meta-Analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078070"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eaat7828","DOI":"10.1126\/sciadv.aat7828","article-title":"Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival","volume":"4","author":"Gast","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8567","DOI":"10.1245\/s10434-021-10379-2","article-title":"Circulating Hybrid Cells: A Novel Liquid Biomarker of Treatment Response in Gastrointestinal Cancers","volume":"28","author":"Walker","year":"2021","journal-title":"Ann. Surg. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Parappilly, M.S., Chin, Y., Whalen, R.M., Anderson, A.N., Robinson, T.S., Strgar, L., Sutton, T.L., Conley, P., Klocke, C., and Gibbs, S.L. (2022). Circulating Neoplastic-Immune Hybrid Cells Predict Metastatic Progression in Uveal Melanoma. Cancers, 14.","DOI":"10.3390\/cancers14194617"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13630","DOI":"10.1038\/s41598-021-93053-7","article-title":"Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors","volume":"11","author":"Dietz","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13045-019-0760-3","article-title":"Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications","volume":"12","author":"Lin","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Pore, A.A., Dhanasekara, C.S., and Navaid HBin Vanapalli, S.A. (2023). Comprehensive Profiling of Cancer-Associated Cells in the Blood of Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy to Predict Pathological Complete Response. Bioegineering, 10.","DOI":"10.3390\/bioengineering10040485"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s10549-017-4372-8","article-title":"Prognostic values of cancer associated macrophage-like cells (CAML) enumeration in metastatic breast cancer","volume":"165","author":"Mu","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sun, N.Y., Chen, Y.L., Wu, W.Y., Lin, H.W., Chiang, Y.C., Chang, C.F., Tai, Y.-J., Hsu, H.-C., Chen, C.-A., and Sun, W.-Z. (2019). Blockade of PD-L1 Enhances Cancer Immunotherapy by Regulating Dendritic Cell Maturation and Macrophage Polarization. Cancers, 11.","DOI":"10.2139\/ssrn.3378678"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1038\/s41598-017-03780-z","article-title":"Image based Machine Learning for identification of macrophage subsets","volume":"7","author":"Rostam","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31726","DOI":"10.1038\/srep31726","article-title":"Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab","volume":"6","author":"Nicolazzo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5233","DOI":"10.1158\/1078-0432.CCR-10-1449","article-title":"M30 Neoepitope Expression in Epithelial Cancer: Quantification of Apoptosis in Circulating Tumor Cells by CellSearch Analysis","volume":"16","author":"Rossi","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lopes, C., Piairo, P., Ch\u00edcharo, A., Abalde-Cela, S., Pires, L.R., Corredeira, P., Alves, P., Muinelo-Romay, L., Costa, L., and Di\u00e9guez, L. (2021). HER2 Expression in Circulating Tumour Cells Isolated from Metastatic Breast Cancer Patients Using a Size-Based Microfluidic Device. Cancers, 13.","DOI":"10.3390\/cancers13174446"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Tang, C.M., and Adams, D.L. (2022). Clinical Applications of Cancer-Associated Cells Present in the Blood of Cancer Patients. 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