Highlight report: Relevance of T-cells, B-cells and immune checkpoint factors for prognosis of breast cancer
Maiju Myllys11IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, GERMANY
EXCLI J 2019;18:Doc253
Recently, Anne-Sophie Heimes and colleagues from the University Hospital of Mainz published a study to gain a better understanding of the association of specific immune responses with prognosis in breast cancer (Heimes et al., 2017). Although it is well established that tumor-infiltrating lymphocytes have prognostic and predictive impact, the specific role of individual cell types is still discussed controversially (Schumacher and Schreiber, 2015; Denkert et al., 2010; Salgado et al., 2015; Iglesia et al., 2016; Rody et al., 2009; Mahmoud et al., 2011). To gain a deeper understanding, 197 node-negative breast carcinomas of patients not treated with adjuvant therapy were analyzed for T-cell and B-cell markers based on gene-expression data by immunostaining (Heimes et al., 2017). Moreover, two immune checkpoint markers, PD-1 and CTLA-4, were analyzed. In a multivariate analysis, infiltration of both T-cells and B-cells was significantly associated with better prognosis. Also the immune checkpoint markers showed a significant association with prognosis, independent of the clinical-pathological variables. Particularly interesting results were obtained after analysis of the molecular subtypes HER2+, basal-like (ER-/ HER2-), luminal A (ER+, HER2-, AURKA-low) and luminal B (ER+, HER2-, AURKA-high). The prognostic effect of immune cells (T- and B-cells) was strongest in the HER2+ molecular subtype. Major differences were obtained between the other molecular subtypes with T-cells most pronounced in the luminal A, B-cells in the luminal B and the immune regulators in basal-like carcinomas.
The positive prognostic influence of lymphocytic infiltrates has been known for decades (Di Paola et al., 1974; Aaltomaa et al., 1992). While the relevance of T-cells has been accepted since long, the key prognostic impact of the humoral immune system has only been reported in 2008 (Schmidt et al., 2008) and the prognostic role of individual cell types and related factor of influence have been further assessed in several studies (Heimes et al., 2017; Schmidt et al., 2018, 2012; Mattsson et al., 2015; Sicking et al., 2014). The situation remains challenging, since only the presence of T- and B-cells in tumor tissue does not seem to be sufficient to guarantee a favorable prognostic influence. Besides lymphocyte infiltration, further factors seem to be relevant, including the redox status, migration capacity, proliferation and the metabolic microenvironment (Hammad et al., 2016; Cadenas et al., 2010, 2014; Marchan et al., 2017; Hassan et al., 2017; Hellwig et al., 2016; Stock et al., 2015; Stewart et al., 2012). A particularly critical aspect is to consider negative immune regulators, such as CTLA-4 and PD-1. In conclusion, the study of Heimes and colleagues (2017) clearly shows that the analysis of tumor infiltrating lymphocytes should at least include differentiation between T-cells, B-cells/plasma cells and negative immune regulators, and should independently consider the four molecular subtypes HER2+, basal-like, luminal A and luminal B.
1. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E, et al. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer. 1992;28:859-64.
2. Cadenas C, Franckenstein D, Schmidt M, Gehrmann M, Hermes M, Geppert B, et al. Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer. Breast Cancer Res. 2010;12(3):R44.
3. Cadenas C, van de Sandt L, Edlund K, Lohr M, Hellwig B, Marchan R, et al. Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle. 2014;13:3282-91.
4. Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105–13.
5. Di Paola M, Angelini L, Bertolotti A, Colizza S. Host resistance in relation to survival in breast cancer. Br Med J. 1974;4(5939):268-70.
6. Hammad S, Mahmoud HY, Hamadneh L, Elsherief AM, Meindl-Beinker NM, Kotb AM. Highlight report: pluripotent stem cells in translational research. Arch Toxicol. 2016;90:3145-6.
7. Hassan R. Highlight report: The EDI3-GPAM axis in tumor cell migration. EXCLI J. 2017;16:1148-9.
8. Heimes AS, Madjar K, Edlund K, Battista MJ, Almstedt K, Gebhard S, et al. Prognostic significance of interferon regulating factor 4 (IRF4) in node-negative breast cancer. J Cancer Res Clin Oncol. 2017;143:1123-31.
9. Hellwig B, Madjar K, Edlund K, Marchan R, Cadenas C, Heimes AS, et al. Epsin family member 3 and ribosome-related genes are associated with late metastasis in estrogen receptor-positive breast cancer and long-term survival in non-small cell lung cancer using a genome-wide identification and validation strategy. PLoS One. 2016;11(12):e0167585.
10. Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM, Vincent BG. Genomic analysis of immune cell infiltrates across 11 tumor types. J Natl Cancer Inst. 2016;108(11):144.
11. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.
12. Marchan R, Büttner B, Lambert J, Edlund K, Glaeser I, Blaszkewicz M, et al. Glycerol-3-phosphate acyltransferase 1 promotes tumor cell migration and poor survival in ovarian carcinoma. Cancer Res. 2017;77:4589-601.
13. Mattsson JS, Bergman B, Grinberg M, Edlund K, Marincevic M, Jirström K, et al. Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression. Cancer Lett. 2015;356:837-45.
14. Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 2009;11(2):R15.
15. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.
16. 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;68:5405-13.
17. Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin κ C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012;18:2695-703.
18. Schmidt M, Weyer-Elberich V, Hengstler JG, Heimes AS, Almstedt K, Gerhold-Ay A, et al. Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population. Breast Cancer Res. 2018;20(1):15.
19. Schumacher T, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.
20. Sicking I, Edlund K, Wesbuer E, Weyer V, Battista MJ, Lebrecht A, et al. Prognostic influence of pre-operative C-reactive protein in node-negative breast cancer patients. PLoS One. 2014;9(10):e111306.
21. Stewart JD, Marchan R, Lesjak MS, Lambert J, Hergenroeder R, Ellis JK, et al. Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis. Proc Natl Acad Sci U S A. 2012;109:8155-60.
22. Stock AM, Klee F, Edlund K, Grinberg M, Hammad S, Marchan R, et al. Gelsolin is associated with longer metastasis-free survival and reduced cell migration in estrogen receptor-positive breast cancer. Anticancer Res. 2015;35:5277-85.