Abstract
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+ plasma cells had significantly better disease-free survival (DFS) (HR = 0.44; 95% CI 0.26–0.77; p = 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 p = 0.029 and DFS p = 0.005). The presence of B cells and plasma cells was positively correlated (p < 0.0001, R = 0.558), while immunoglobulin gene IGKC, IGHM, and IGHG1 mRNA expression correlated specifically with the density of CD38+ plasma cells (IGKC p < 0.0001, R = 0.647; IGHM p < 0.0001, R = 0.580; IGHG1 p < 0.0001, R = 0.655). Interestingly, after adjusting the multivariate analysis for the effect of intratumoral CD38+ 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+ plasma cell density to clinicopathological features significantly increased the prognostic value for both DFS (ΔLRχ2 = 17.28, p = 1.71E−08) and OS (ΔLRχ2 = 10.03, p = 6.32E−08), compared to clinicopathological features alone. The best combination was achieved by integrating intratumoral CD38+ plasma cell density and IGHG1 which conferred the best added prognostic value for DFS (ΔLRχ2 = 27.38, p = 5.22E−10) and OS (ΔLRχ2 = 21.29, p = 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.
Highlights
Breast cancer is the most common malignancy in women, affecting approximately 12% of females during their lifetimes [1]
Previous studies have relied upon CD138 as a plasma cell marker, as this molecule is expressed on some tumor cells, we used CD38 to discriminate plasma cells within tumors [54,55,56,57]
We found that expression levels of these three genes significantly and positively correlated with the abundance of CD38+ plasma cells in our Triple negative breast cancers (TNBCs) samples (IGKC p < 0.0001, R = 0.647; IGHM p < 0.0001, R = 0.580; IGHG1 p < 0.0001, R = 0.655, Table S3 in Supplementary Material); and were associated with incrementally increasing Disease-free survival (DFS) in multivariate analysis adjusted for tumor size, grade, age, and lymph node status (Table 5)
Summary
Breast cancer is the most common malignancy in women, affecting approximately 12% of females during their lifetimes [1]. Triple negative breast cancers (TNBCs), defined by the absence of hormone receptor (estrogen receptor, progesterone receptor) and cerbB2 (HER2) expression, constitute about 15–20% of all breast cancers [2,3,4] They pose significant management challenges due to the lack of effective treatment options and often exhibit aggressive clinical behavior [5,6,7,8,9]. Compared to other breast cancer subtypes, TNBCs exhibit more abundant lymphoid cell infiltrates; various components of which have been variably correlated with better or worse prognosis [10,11,12,13,14,15]. Future progress will require us to understand the full suite of immune cells present in the tumor, their relative abundance, and their functional profile, in order to paint a complete picture of tumor-immune interactions and their effects on disease outcome
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