Immunopathological Mechanisms Observed in the Intratumoral Microenvironment and Their Relationship with Worse Prognosis in Triple-Negative Breast Cancer Immunopathological mechanisms in TNBC

Josué Mondragón Morales (1), Rogelio Rogel-Alvarado (2), Iris Alejandra Noverón-Figueroa (3), Max Morales-Gutierrez (4)
(1) Escuela Superior de Medicina, Instituto Politécnico Nacional, Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomás, México City, México, Mexico,
(2) Facultad de Enfermería y Obstetricia, Universidad Nacional Autónoma de México, Camino Viejo a Xochimilco y Viaducto Tlalpan S/N. San Lorenzo Huipulco, Tlalpan, México City, México, Mexico,
(3) Escuela Superior de Medicina, Instituto Politécnico Nacional, Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomás, México City, México, Mexico,
(4) Universidad Westhill, Domingo García Ramos Nº 56, Cuajimalpa Col. Prados de la Montaña, México City, México, Mexico


Background: In the 21st century, the main cause of death in both sexes worldwide is cardiovascular disease, followed by neoplasms. In women, the main cause of morbidity and mortality is breast cancer. Therefore, understanding the immunological mechanisms associated breast cancer and its correlation with poor prognosis is very important.

Methods: In this study, a search was done on PubMed and Google Scholar, using the following medical subject headings (MeSH) in the search engine: “triple negative breast cancer”, “breast cancer microenvironment”, “immune cells”, “prognosis”, “regulatory t reg”, “T cells” and “tumor-associated neutrophils”. Thus, a total of 81 articles were found and reviewed, published between 2002 and 2023.

Results and conclusions: It is essential to understand the immunological mechanisms associated with the tumor microenvironment, to create new targeted treatment schemes for each variant of breast cancer, for example triple negative in order to reduce the mortality rate and increase disease-free survival. 

Full text article

Generated from XML file


Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492.

Liu Z, Jiang Z, Wu N, Zhou G, Wang X. Classification of triple-negative breast cancers based on immunogenomic profiling. Journal of Experimental and Clinical Cancer Research. 2021;14(1):1–13. doi: 10.1186/s13046-018-1002-1.

Oner G, Altintas S, Canturk Z, Tjalma W, Verhoeven Y, Van Berckelaer C, et al. Triple-negative breast cancer—Role of immunology: A systemic review. Breast Journal. 2020;26(5):995–9. doi: 10.1111/tbj.13696.

Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Research. 2020;22(1):1–13. doi: 10.1186/s13058-020-01296-5.

Arneth B. Tumor Microenvironment. Medicina. 2020;56(1):15. doi: 10.3390/medicina56010015.

Tavares MC, Sampaio CD, Lima GE, Andrade VP, Gonçalves DG, Macedo MP, et al. A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma. BMC Cancer. 2021;21(1):1–12. doi: 10.1186/s12885-021-08636-4.

Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31–46. doi: 10.1158/2159-8290.CD-21-1059.

Deng L, Lu D, Bai Y, Wang Y, Bu H, Zheng H. Immune profiles of tumor microenvironment and clinical prognosis among women with triple-negative breast cancer. Cancer Epidemiology Biomarkers and Prevention. 2019;28(12):1977–85. doi: 10.1158/1055-9965.EPI-19-0469.

Liubomirski Y, Lerrer S, Meshel T, Rubinstein-Achiasaf L, Morein D, Wiemann S, et al. Tumor-stroma-inflammation networks promote pro-metastatic chemokines and aggressiveness characteristics in triple-negative breast cancer. Front Immunol. 2019; 10:1–24. doi: 10.3389/fimmu.2019.00757.

Wu SZ, Roden DL, Wang C, Holliday H, Harvey K, Cazet AS, et al. Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer. EMBO J. 2020;39(19):1–20. doi: 10.15252/embj.2019104063.

Wang X, Su W, Tang D, Jing J, Xiong J, Deng Y, et al. An immune-related gene prognostic index for triple-negative breast cancer integrates multiple aspects of tumor-immune microenvironment. Cancers (Basel). 2021;13(21). doi: 10.3390/cancers13215342.

Graeser M, Feuerhake F, Gluz O, Volk V, Hauptmann M, Jozwiak K, et al. Immune cell composition and functional marker dynamics from multiplexed immunohistochemistry to predict response to neoadjuvant chemotherapy in the WSG-ADAPT-TN trial. J Immunother Cancer. 2021;9(5):1–11. doi: 10.1136/jitc-2020-002198.

Xiao Y, Ma D, Zhao S, Suo C, Shi J, Xue MZ, et al. Multi-omics profiling reveals distinct microenvironment characterization and suggests immune escape mechanisms of triple-negative breast cancer. Clinical Cancer Research. 2019;25(16):5002–14. doi: 10.1158/1078-0432.CCR-18-3524.

Liu Z, Li M, Jiang Z, Wang X. A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer. Transl Oncol. 2018;11(2):311–29. doi: 10.1016/j.tranon.2018.01.011.

Zhang Y, Tian J, Qu C, Tang Z, Wang Y, Li K, et al. Prognostic value of programmed cell death ligand-1 expression in breast cancer: A meta-analysis. Medicine (United States). 2020;99(49):E23359. doi: 10.1097/MD.0000000000023359.

Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and survival in solid tumors: A meta-analysis. PLoS One. 2015;10(6):1–15. doi: 10.1371/journal.pone.0131403.

Muazzam Nasrullah 2018, Hu J, Cui W, Ding W, Gu Y, Wang Z, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Physiol Behav. 2016;176(1):139–48. doi: 10.1038/s41591-018-0136-1.

Loi S, Michiels S, Adams S, Loibl S, Budczies J, Denkert C, et al. The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: clinical utility in an era of checkpoint inhibition. Annals of Oncology. 2021;32(10):1236–44. doi: 10.1016/j.annonc.2021.07.007.

Stovgaard ES, Nielsen D, Hogdall E, Balslev E. Triple negative breast cancer–prognostic role of immune-related factors: a systematic review. Acta Oncol (Madr). 2018;57(1):74–82. doi: 10.1080/0284186X.2017.1400180.

Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080–9. doi: 10.1111/cas.14069.

Jamiyan T, Kuroda H, Yamaguchi R, Nakazato Y, Noda S, Onozaki M, et al. Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast. Breast Cancer. 2020;27(5):880–92. doi: 10.1007/s12282-020-01084-1

Shaul ME, Levy L, Sun J, Mishalian I, Singhal S, Kapoor V, et al. Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology. 2016;5(11):1–14. doi: 10.1080/2162402X.2016.1232221.

Winter A, Becker J, Loehl F, Rehlich K, Simrock S, Tege P. Myeloid-derived-suppressor cells as regulators of the immune system. Nat Rev Immunol. 2006;9(3):565–7. doi: 10.1038/nri2506

Vidotto T, Saggioro FP, Jamaspishvili T, Chesca DL, Picanço de Albuquerque CG, Reis RB, et al. PTEN-deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells. Prostate. 2019;79(9):969–79. doi: 10.1002/pros.23808.

Kurozumi S, Fujii T, Matsumoto H, Inoue K, Kurosumi M, Horiguchi J, et al. Significance of evaluating tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in breast cancer. Med Mol Morphol. 2017;50(4):185–94. doi: 10.1007/s00795-017-0170-y.

Zhang L, Wang XI, Ding J, Sun Q, Zhang S. The predictive and prognostic value of Foxp3+/CD25+ regulatory T cells and PD-L1 expression in triple negative breast cancer. Ann Diagn Pathol. 2019;40:143–51. doi: 10.1016/j.anndiagpath.2019.04.004.

Gajewski TF, Corrales L, Williams J, Horton B, Sivan A, Spranger S. Cancer immunotherapy targets based on understanding the t cell-inflamed versus non-t cell-inflamed tumor microenvironment. Adv Exp Med Biol. 2017;1036:19–31. doi: 10.1007/978-3-319-67577-0_2.

Yu P, Fu YX. Tumor-infiltrating T lymphocytes: Friends or foes? Laboratory Investigation. 2006;86(3):231–45. doi: 10.1038/labinvest.3700389.

He L, Wang Y, Wu Q, Song Y, Ma X, Zhang B, et al. Association between levels of tumor-infiltrating lymphocytes in different subtypes of primary breast tumors and prognostic outcomes: A meta-analysis. BMC Womens Health. 2020;20(1):1–11. doi: 10.1186/s12905-020-01038-x.

Gao G, Wang Z, Qu X, Zhang Z. Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: A systematic review and meta-analysis. BMC Cancer. 2020;20(1). doi: 10.1186/s12885-020-6668-z

Wang K, Shen T, Siegal GP, Wei S. The CD4/CD8 ratio of tumor-infiltrating lymphocytes at the tumor-host interface has prognostic value in triple-negative breast cancer. Hum Pathol. 2017;69:110–7. doi: 10.1016/j.humpath.2017.09.012.

Ibrahim EM, Al-Foheidi ME, Al-Mansour MM, Kazkaz GA. The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis. Breast Cancer Res Treat. 2014;148(3):467–76. doi: 10.1186/s12885-020-6668-z.

Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI. Mechanism of T Cell Tolerance Induced by Myeloid-Derived Suppressor Cells. The Journal of Immunology. 2010;184(6):3106–16. doi: 10.4049/jimmunol.0902661.

Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19(1):40–50. doi: 10.1016/S1470-2045(17)30904-X.

Annaratone L, Cascardi E, Vissio E, Sarotto I, Chmielik E, Sapino A, et al. The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas. Pathobiology. 2020;87(2):125–42. doi: 10.1159/000507055.

van den Ende NS, Nguyen AH, Jager A, Kok M, Debets R, van Deurzen CHM. Triple-Negative Breast Cancer and Predictive Markers of Response to Neoadjuvant Chemotherapy: A Systematic Review. Int J Mol Sci. 2023;24(3). doi: 10.3390/ijms24032969.

Fionnuala P. O’Connell M, Jack L. Pinkus P, Geraldine S. Pinkus M. CD138 (Syndecan-1), a Plasma Cell Marker Immunohistochemical Profile in Hematopoietic and Nonhematopoietic Neoplasms. American Society for Clinical Pathology. 2004;121:254–63. doi: 10.1309/617D-WB5G-NFWX-HW4L.

Mukunyadzi P, Sanderson RD, Fan CY, Smoller BR. The level of syndecan-1 expression is a distinguishing feature in behavior between keratoacanthoma and invasive cutaneous squamous cell carcinoma. Modern Pathology. 2002;15(1):45–9. doi: 10.1038/modpathol.3880488.

Yeong J, Lim JCT, Lee B, Li H, Chia N, Ong CCH, et al. High densities of tumor-associated plasma cells predict improved prognosis in triple negative breast cancer. Front Immunol. 2018;9:2–11. doi: 10.3389/fimmu.2018.01209.

Kuroda H, Jamiyan T, Yamaguchi R, Kakumoto A, Abe A, Harada O, et al. Tumor-infiltrating B cells and T cells correlate with postoperative prognosis in triple-negative carcinoma of the breast. BMC Cancer. 2021;21(1):1–10. doi: 10.1186/s12885-021-08009-x

Hanker LC, Rody A, Holtrich U, Pusztai L, Ruckhaeberle E, Liedtke C, et al. Prognostic evaluation of the B cell/IL-8 metagene in different intrinsic breast cancer subtypes. Breast Cancer Res Treat. 2013;137(2):407–16. doi: 10.1007/s10549-012-2356-2.

Alistar A, Chou JW, Nagalla S, Black MA, D’Agostino R, Miller LD. Dual roles for immune metagenes in breast cancer prognosis and therapy prediction. Genome Med. 2014;6(10):1–12. doi: 10.1186/s13073-014-0080-8.

McDaniel JR, Pero SC, Voss WN, Shukla GS, Sun Y, Schaetzle S, et al. Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node. Cancer Immunology, Immunotherapy. 2018;67:729–38. doi: 10.1186/s13073-014-0080-8.

Harris RJ, Cheung A, Ng JCF, Laddach R, Chenoweth AM, Crescioli S, et al. Tumor-infiltrating B lymphocyte profiling identifies IgG-biased, clonally expanded prognostic phenotypes in triple-negative breast cancer. Cancer Res. 2021;81(16):4290–304. doi: 10.1158/0008-5472.CAN-20-3773.

Yangguang Ou, Rachael E Wilson and SGW. Immunosuppressive plasma cells impede T cell-dependent immunogenic chemotherapy. Annu Rev Anal Chem (Palo Alto Calif). 2018;11(1):509–33. doi: 10.1038/nature14395.

Chaher N, Qualls C, Joste N, Colpaert C, Marotti D, Foisey M, et al. The combined presence of CD20+ B cells and PD-L1+ tumor infiltrating lymphocytes in inflammatory breast cancer is prognostic of improved patient outcome. Breast Cancer Res Treat. 2018;171(2):273–82. doi: 10.1007/s10549-018-4834-7.

Yeong J, Thike AA, Lim JCT, Lee B, Li H, Wong SC, et al. Higher densities of Foxp3+ regulatory T cells are associated with better prognosis in triple-negative breast cancer. Breast Cancer Res Treat. 2017;163(1):21–35. doi: 10.1007/s10549-017-4161-4.

Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, et al. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses. Immunity. 2015;43(3):579–90. doi: 10.1016/j.immuni.2015.08.006.

Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor-infiltrating lymphocytes and prognosis: A pooled individual patient analysis of early-stage triple-negative breast cancers. Journal of Clinical Oncology. 2019;37(7):559–69. doi: 10.1200/JCO.18.01010

Matsumoto H, Koo SL, Dent R, Tan PH, Iqbal J. Role of inflammatory infiltrates in triple negative breast cancer. J Clin Pathol. 2015;68(7):506–10. doi: 10.1136/jclinpath-2015-202944.

Gonzalez-Ericsson PI, Stovgaard ES, Sua LF, Reisenbichler E, Kos Z, Carter JM, et al. The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice. Journal of Pathology. 2020;250(5):667–84. doi: 10.1002/path.5406.

Paredes J, Correia AL, Ribeiro AS, Milanezi F, Cameselle-Teijeiro J, Schmitt FC. Breast carcinomas that co-express E- and P-cadherin are associated with p120-catenin cytoplasmic localisation and poor patient survival. J Clin Pathol. 2008;61(7):856–62. doi: 10.1136/jcp.2007.052704.

Mamessier E, Sylvain A, Bertucci F, Castellano R, Finetti P, Houvenaeghel G, et al. Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition. Cancer Res. 2011;71(21):6621–32. doi: 10.1158/0008-5472.CAN-11-0792.

Blackley EF, Loi S. Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC). Breast. 2019;48:S44–8. doi: 10.1016/S0960-9776(19)31122-1.

Tomioka N, Azuma M, Ikarashi M, Yamamoto M, Sato M, Watanabe K ichi, et al. The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC). Breast Cancer. 2018;25(1):34–42. doi: 10.1007/s12282-017-0781-0.

Oleinika K, Nibbs RJ, Graham GJ, Fraser AR. Suppression, subversion and escape: The role of regulatory T cells in cancer progression. Clin Exp Immunol. 2013;171(1):36–45. doi: 10.1111/j.1365-2249.2012.04657.x

Schmidt M, Böhm D, Von Törne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68(13):5405–13. doi: 10.1158/0008-5472.CAN-07-5206.

Schmidt M, Micke P, Gehrmann M, Hengstler JG. Immunoglobulin kappa chain as an immunologic biomarker of prognosis and chemotherapy response in solid tumors. Oncoimmunology. 2012;1(7):1156–8. doi: 10.4161/onci.21653

Hauser AE, Höpken UE. B Cell Localization and Migration in Health and Disease. Second Edi. Molecular Biology of B Cells: Second Edition. Elsevier Ltd; 2015. 187–214 p. doi: 10.1016/B978-0-12-397933-9.00012-6

Allison E, Edirimanne S, Matthews J, Fuller SJ. Breast Cancer Survival Outcomes and Tumor-Associated Macrophage Markers: A Systematic Review and Meta-Analysis. Oncol Ther. 2023;11(1):27–48. doi: 10.1007/s40487-022-00214-3.

Kuroda H, Jamiyan T, Yamaguchi R, Kakumoto A, Abe A, Harada O, et al. Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes. Clinical and Translational Oncology. 2021;23(12):2513–25. doi: 10.1007/s12094-021-02652-3.

Elham Azizi, Ambrose J. Carr, George Plitas, Andrew E. Cornish, Catherine Konopacki, Prabhakaran S, et al. Single-cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment. Cell. 2018;174(5):1293–308. doi: 10.1016/j.cell.2018.05.060.

Chung W, Eum HH, Lee HO, Lee KM, Lee HB, Kim KT, et al. Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer. Nat Commun. 2017;8:1–12. doi: 10.1038/ncomms15081.

Bao X, Shi R, Zhao T, Wang Y, Anastasov N, Rosemann M, et al. Integrated analysis of single-cell RNA-seq and bulk RNA-seq unravels tumour heterogeneity plus M2-like tumour-associated macrophage infiltration and aggressiveness in TNBC. Cancer Immunology, Immunotherapy. 2021;70(1):189–202. doi: 10.1007/s00262-020-02669-7.

Tan W, Liu M, Wang L, Guo Y, Wei C, Zhang S, et al. Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer. BMC Cancer. 2021;21(1):1–16. doi: 10.1186/s12885-021-07837-1.

Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A, et al. A single-cell and spatially resolved atlas of human breast cancers. Nat Genet. 2021;53(9):1334–47. doi: 10.1038/s41588-021-00911-1.

Shinohara H, Kobayashi M, Hayashi K, Nogawa D, Asakawa A, Ohata Y, et al. Spatial and Quantitative Analysis of Tumor-Associated Macrophages: Intratumoral CD163-/PD-L1+ TAMs as a Marker of Favorable Clinical Outcomes in Triple-Negative Breast Cancer. Int J Mol Sci. 2022;23(21):1–14. doi: 10.3390/ijms232113235.

Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, et al. The combination of PD-L1 expression and decreased tumorinfiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer. Oncotarget. 2017;8(9):15584–92. doi: 10.18632/oncotarget.14698.

Wang Z, Yang C, Li L, Jin X, Zhang Z, Zheng H, et al. Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer. Oncogenesis. 2020;9(9). doi: 10.1038/s41389-020-00267-x

Takai K, Le A, Weaver VM, Werb Z. Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget. 2016;7(50):82889–901. doi: 10.18632/oncotarget.12658.

Young Hee Choi and AMY, Das C Hansen KC and Tyler JK LMS, Chizuko Yamamuro, Jian-Kang Zhu ZY, Maxson & Mitchell, Rooks, M.G and Garrett, W.S, MUELLER. Increased expression of Beige/Brown adipose markers from host and breast cancer cells influence xenograft formation in mice. Physiol Behav. 2017;176(3):139–48. doi: 10.1158/1541-7786.MCR-15-0151.

Nieman KM, Kenny HA, Penicka C V., Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498–503. doi: 10.1038/nm.2492.

Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71(7):2455–65. doi: 10.1158/0008-5472.CAN-10-3323.

Zhang X, Zeng Y, Qu Q, Zhu J, Liu Z, Ning W, et al. PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol. 2017;22(6):1026–33. doi: 10.1007/s10147-017-1161-7.

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Albright A, et al. IFN-y-related MRNA profile predicts clinical response to PD-1 blockade. Journal of Clinical Investigation. 2017;127(8). doi: 10.1172/JCI91190.

SenGupta S, Hein LE, Xu Y, Zhang J, Konwerski JR, Li Y, et al. Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands. Front Immunol. 2021;12:1–20. doi: 10.3389/fimmu.2021.659996.

Cell N, Author B, February PMC, Kim IS, Gao Y, Welte T, et al. Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms. Nat Cell Biol. 2020;21(9):1113–26. doi: 10.1038/s41556-019-0373-7.

Zheng C, Xu X, Wu M, Xue L, Zhu J, Xia H, et al. Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance. Breast Cancer Research. 2023;25(1):1–12. doi: 10.1186/s13058-023-01676-7

Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Worthen GS, et al. Polarization of TAN phenotype by TGFb: “N1” versus “N2” TAN. Cancer Cell. 2010;16(3):183–94. doi: 10.1016/j.ccr.2009.06.017.

Delayre T, Guilbaud T, Resseguier N, Mamessier E, Rubis M, Moutardier V, et al. Prognostic impact of tumour-infiltrating lymphocytes and cancer-associated fibroblasts in patients with pancreatic adenocarcinoma of the body and tail undergoing resection. British Journal of Surgery. 2020;107(6):720–33. doi: 10.1002/bjs.11434

Bartoschek M, Oskolkov N, Bocci M, Lövrot J, Larsson C, Sommarin M, et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat Commun. 2018;9(1). doi: 10.1038/s41467-018-07582-3.

Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell. 2018;33(3):463-479.e10. doi: 10.1016/j.ccell.2018.01.011.

Sebastian A, Hum NR, Martin KA, Gilmore SF, Peran I, Byers SW, et al. Single-Cell Transcriptomic Analysis of Heterogeneity in Breast Cancer. Cancers (Basel). 2020;12(5):E1307. doi: 10.3390/cancers12051307.

Valdés-Mora F, Salomon R, Gloss BS, Law AMK, Venhuizen J, Castillo L, et al. Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype. Cell Rep. 2021;35(2). doi: 10.1016/j.celrep.2021.108945.

Kieffer Y, Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020;10(9):1330–51. doi: 10.1158/2159-8290.CD-19-1384.

Zhang W, Xu J, Fang H, Tang L, Chen W, Sun Q, et al. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling. The FASEB Journal. 2018;32(1):276–88. doi: 10.1096/fj.201700237RR

Acerbi I, Cassereau L, Dean I, Shi Q, Au A, Park C, et al. Human Breast Cancer Invasion and Aggression Correlates with ECM Stiffening and Immune Cell Infiltration. Integr Biol (Camb). 2015;7(10):1120. doi: 10.1039/c5ib00040h

Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013;22 Suppl 2(S2). doi: 10.1016/j.breast.2013.07.012.

Kaushik S, Pickup MW, Weaver VM. From transformation to metastasis: deconstructing the extracellular matrix in breast cancer. Cancer Metastasis Rev. 2016; 35(4):655. doi: 10.1007/s10555-016-9650-0

Lee J. Current Treatment Landscape for Early Triple-Negative Breast Cancer (TNBC). J Clin Med. 2023;12(4):1524. doi: 10.3390/jcm12041524.

Zerdes I, Matikas A, Bergh J, Rassidakis GZ, Foukakis T. Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene. Nature Publishing Group; 2018;37: 4639–61. doi: 10.1038/s41388-018-0303-3.

Muller K, Jorns JM, Tozbikian G. What’s new in breast pathology 2022: WHO 5th edition and biomarker updates. J Pathol Transl Med. 2022;56(3):170. doi: 10.4132/jptm.2022.04.25

Barchiesi G, Roberto M, Verrico M, Vici P, Tomao S, Tomao F. Emerging Role of PARP Inhibitors in Metastatic Triple Negative Breast Cancer. Current Scenario and Future Perspectives. Front Oncol. 2021;11:769280. doi: 10.3389/fonc.2021.769280

Cortes J, Haiderali A, Huang M, Pan W, Schmid P, Akers KG, et al. Neoadjuvant immunotherapy and chemotherapy regimens for the treatment of high-risk, early-stage triple-negative breast cancer: a systematic review and network meta-analysis. BMC Cancer. 2023;23(1). doi: 10.1186/s12885-023-11293-4.

Waldeland JO, Gaustad JV, Rofstad EK, Evje S. In silico investigations of intratumoral heterogeneous interstitial fluid pressure. J Theor Biol. 2021;526:110787. doi: 10.1016/j.jtbi.2021.110787.

Hu J, Zhang L, Xia H, Yan Y, Zhu X, Sun F, et al. Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing. Genome Med. 2023;15(1):1–25. doi: 10.1186/s13073-023-01164-9

Barker HE, Paget JTE, Khan AA, Harrington KJ. The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence. Nat Rev Cancer. 2015;15(7):409. doi: 10.1038/nrc3958.

Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway. Science. 2013;339(6121):786–91. doi: 10.1126/science.1232458.

Kuehnemuth B, Piseddu I, Wiedemann GM, Lauseker M, Kuhn C, Hofmann S, et al. CCL1 is a major regulatory T cell attracting factor in human breast cancer. BMC Cancer. 2018;18(1). doi: 10.1186/s12885-018-5117-8.

Park YH, Lal S, Lee JE, Choi Y La, Wen J, Ram S, et al. Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome. Nat Commun. 2020;11(1). doi: 10.1038/s41467-020-19933-0.


Josué Mondragón Morales (Primary Contact)
Rogelio Rogel-Alvarado
Iris Alejandra Noverón-Figueroa
Max Morales-Gutierrez
Mondragón Morales J, Rogel-Alvarado R, Noverón-Figueroa IA, Morales-Gutierrez M. Immunopathological Mechanisms Observed in the Intratumoral Microenvironment and Their Relationship with Worse Prognosis in Triple-Negative Breast Cancer: Immunopathological mechanisms in TNBC. Arch Breast Cancer [Internet]. 2024 Jan. 31 [cited 2024 Feb. 22];11(1):1-12. Available from:

Article Details