38cc222d01b856f6c2e7db1f5e52e9ad pmc_10932208.pdf 958cca826218c0861ef70797bb7ce028af2503b0 pmc_10932208.pdf e4ad7b6ddc199c81641027062296e033cd58a21c23242c29b5191e3d27c326e8 pmc_10932208.pdf Title: Clinical Relevance of Tumour-Infiltrating Immune Cells in HER2-Negative Breast Cancer Treated with Neoadjuvant Therapy Subject: Currently, therapy response cannot be accurately predicted in HER2-negative breast cancer (BC). Measuring stromal tumour-infiltrating lymphocytes (sTILs) and mediators of the tumour microenvironment and characterizing tumour-infiltrating immune cells (TIICs) may improve treatment response in the neoadjuvant setting. Tumour tissue and peripheral blood samples were retrospectively collected from 118 patients, and sTILs were evaluated. Circulating exosomes and myeloid-derived suppressor cells were determined by flow cytometry. TIICs markers (CD4, CD8, CD20, CD1a, and CD68) were assessed immunohistochemically. High sTILs were significantly associated with pathological complete response (pCR; p = 0.048) and event-free survival (EFS; p = 0.027). High-CD68 cells were significantly associated with pCR in triple-negative (TN, p = 0.027) and high-CD1a cells with EFS in luminal-B (p = 0.012) BC. Cluster analyses of TIICs revealed two groups of tumours (C1 and C2) that had different immune patterns and clinical outcomes. An immunoscore based on clinicopathological variables was developed to identify high risk (C1) or low-risk (C2) patients. Additionally, cluster analyses revealed two groups of tumours for both luminal-B and TNBC. Our findings support the association of sTILs with pCR and show an immunological component in a subset of patients with HER2-negative BC. Our immunoscore may be useful for future escalation or de-escalation treatments. Keywords: breast cancer; neoadjuvant chemotherapy; stromal tumour-infiltrating lymphocytes; tumour-infiltrating immune cells Author: Cristina Arqueros, Alberto Gallardo, Silvia Vidal, Rubén Osuna-Gómez, Ariadna Tibau, Olga Lidia Bell, Teresa Ramón y Cajal, Enrique Lerma, Bárbara Lobato-Delgado, Juliana Salazar and Agustí Barnadas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Mon Feb 26 01:57:49 2024 CET ModDate: Mon Feb 26 05:09:08 2024 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1649532 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JYPLJJ+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 MZAOGE+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 EEMHXY+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 EXYWVU+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 LWJOET+VnURWPalladioL Type 1 Custom yes yes yes 32 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 48 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 QLADRS+CMSY10 Type 1 Builtin yes yes yes 71 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 79 0 OVNEXW+EURM10 Type 1 Builtin yes yes yes 126 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-04-26 02:41:02 CEST RepresentationInformation: pmc_10932208.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-04-24 02:31:41 CEST Size: 1649532 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 336 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Patients’ Characteristics Destination: subsection.2.1 Item: Title: sTILs and Clinicopathological Features Destination: subsection.2.2 Item: Title: sTILs as Predictive Biomarkers Destination: subsection.2.3 Item: Title: sTILs as Prognostic Biomarker Destination: subsection.2.4 Item: Title: Systemic Expression Biomarkers Destination: subsection.2.5 Item: Title: TIICs and Outcomes Destination: subsection.2.6 Item: Title: Clustering TIICs Destination: subsection.2.7 Item: Title: Immunoscore Destination: subsection.2.8 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Patient Population and Outcome Evaluation Destination: subsection.4.1 Item: Title: sTILs Assessment Destination: subsection.4.2 Item: Title: Immunohistochemistry of TIICs Destination: subsection.4.3 Item: Title: MDSCs Analysis Destination: subsection.4.4 Item: Title: Isolation of Exosomes Destination: subsection.4.5 Item: Title: Statistical Analyses Destination: subsection.4.6 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: Clinical Relevance of Tumour-Infiltrating Immune Cells in HER2-Negative Breast Cancer Treated with Neoadjuvant Therapy Author: Cristina Arqueros, Alberto Gallardo, Silvia Vidal, Rubén Osuna-Gómez, Ariadna Tibau, Olga Lidia Bell, Teresa Ramón y Cajal, Enrique Lerma, Bárbara Lobato-Delgado, Juliana Salazar and Agustí Barnadas Subject: Currently, therapy response cannot be accurately predicted in HER2-negative breast cancer (BC). Measuring stromal tumour-infiltrating lymphocytes (sTILs) and mediators of the tumour microenvironment and characterizing tumour-infiltrating immune cells (TIICs) may improve treatment response in the neoadjuvant setting. Tumour tissue and peripheral blood samples were retrospectively collected from 118 patients, and sTILs were evaluated. Circulating exosomes and myeloid-derived suppressor cells were determined by flow cytometry. TIICs markers (CD4, CD8, CD20, CD1a, and CD68) were assessed immunohistochemically. High sTILs were significantly associated with pathological complete response (pCR; p = 0.048) and event-free survival (EFS; p = 0.027). High-CD68 cells were significantly associated with pCR in triple-negative (TN, p = 0.027) and high-CD1a cells with EFS in luminal-B (p = 0.012) BC. Cluster analyses of TIICs revealed two groups of tumours (C1 and C2) that had different immune patterns and clinical outcomes. An immunoscore based on clinicopathological variables was developed to identify high risk (C1) or low-risk (C2) patients. Additionally, cluster analyses revealed two groups of tumours for both luminal-B and TNBC. Our findings support the association of sTILs with pCR and show an immunological component in a subset of patients with HER2-negative BC. Our immunoscore may be useful for future escalation or de-escalation treatments. 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