AUTHOR=Yeong Joe , Lim Jeffrey Chun Tatt , Lee Bernett , Li Huihua , Chia Noel , Ong Clara Chong Hui , Lye Weng Kit , Putti Thomas Choudary , Dent Rebecca , Lim Elaine , Thike Aye Aye , Tan Puay Hoon , Iqbal Jabed 

TITLE=High Densities of Tumor-Associated Plasma Cells Predict Improved Prognosis in Triple Negative Breast Cancer

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01209

DOI=10.3389/fimmu.2018.01209

ISSN=1664-3224

ABSTRACT=<p>Breast cancer is the most common malignancy affecting women, but the heterogeneity of the condition is a significant obstacle to effective treatment. Triple negative breast cancers (TNBCs) do not express HER2 or the receptors for estrogen or progesterone, and so often have a poor prognosis. Tumor-infiltrating T cells have been well-characterized in TNBC, and increased numbers are associated with better outcomes; however, the potential roles of B cells and plasma cells have been large. Here, we conducted a retrospective correlative study on the expression of B cell/plasma cell-related genes, and the abundance and localization of B cells and plasma cells within TNBCs, and clinical outcome. We analyzed 269 TNBC samples and used immunohistochemistry to quantify tumor-infiltrating B cells and plasma cells, coupled with NanoString measurement of expression of immunoglobulin metagenes. Multivariate analysis revealed that patients bearing TNBCs with above-median densities of CD38<sup>+</sup> plasma cells had significantly better disease-free survival (DFS) (HR = 0.44; 95% CI 0.26–0.77; <italic>p</italic> = 0.004) but not overall survival (OS), after adjusting for the effects of known prognostic factors. In contrast, TNBCs with higher immunoglobulin gene expression exhibited improved prognosis (OS <italic>p</italic> = 0.029 and DFS <italic>p</italic> = 0.005). The presence of B cells and plasma cells was positively correlated (<italic>p</italic> &lt; 0.0001, <italic>R</italic> = 0.558), while immunoglobulin gene IGKC, IGHM, and IGHG1 mRNA expression correlated specifically with the density of CD38<sup>+</sup> plasma cells (IGKC <italic>p</italic> &lt; 0.0001, <italic>R</italic> = 0.647; IGHM <italic>p</italic> &lt; 0.0001, <italic>R</italic> = 0.580; IGHG1 <italic>p</italic> &lt; 0.0001, <italic>R</italic> = 0.655). Interestingly, after adjusting the multivariate analysis for the effect of intratumoral CD38<sup>+</sup> plasma cell density, the expression levels of all three genes lost significant prognostic value, suggesting a biologically important role of plasma cells. Last but not least, the addition of intratumoral CD38<sup>+</sup> plasma cell density to clinicopathological features significantly increased the prognostic value for both DFS (ΔLRχ<sup>2</sup> = 17.28, <italic>p</italic> = 1.71E−08) and OS (ΔLRχ<sup>2</sup> = 10.03, <italic>p</italic> = 6.32E−08), compared to clinicopathological features alone. The best combination was achieved by integrating intratumoral CD38<sup>+</sup> plasma cell density and IGHG1 which conferred the best added prognostic value for DFS (ΔLRχ<sup>2</sup> = 27.38, <italic>p</italic> = 5.22E−10) and OS (ΔLRχ<sup>2</sup> = 21.29, <italic>p</italic> = 1.03E−08). Our results demonstrate that the role of plasma cells in TNBC warrants further study to elucidate the relationship between their infiltration of tumors and disease recurrence.</p>