Landscape of infiltrating B cells and their clinical significance in human hepatocellular carcinoma

Oncoimmunology. 2019 Feb 7;8(4):e1571388. doi: 10.1080/2162402X.2019.1571388. eCollection 2019.

Abstract

As a major cellular component in tumor microenvironment, the distribution, frequency, and prognostic significance of infiltrating B cell subsets in hepatocellular carcinoma (HCC) remain controversial. Using tyramide signal amplification (TSA) based fluorescent multiplexed immunohistochemistry in situ, we evaluated the distribution and frequency of B cell subsets in two independent HCC cohorts (n = 619). The results were further confirmed by flow cytometry. Correlations of B cell subsets with clinicopathologic features and patient prognosis were analyzed. Five B cell subsets were defined by multiplexed immunohistochemistry and each subset was clearly separated by t-SNE dimension reduction analysis. Notably, the densities of all B cell subsets were significantly decreased in the tumor. The frequency of plasma cells within B cells was most abundant in the tumor. In training cohort (n = 258), high densities of tumor-infiltrating CD20+ B cells, naive B cells, IgM+ memory B cells, CD27- isotype-switched memory B cells, and plasma cells were associated with superior survival. Multivariate analysis further identified CD20+ B cells, naive B cells, and CD27- isotype-switched memory B cells as independent prognosticators for survival. Unsupervised cluster analysis confirmed increased B cell subsets harbored superior survival. In addition, high density of B cells was correlated with smaller tumor size and well differentiation. The results were validated in the independent cohort of 361 HCC patients. Intratumor infiltration of B cells is significantly impaired during HCC progression. High densities of tumor-infiltrating B cells imply a better clinical outcome. Therapies designed to target B cells may be a novel strategy in HCC.

Keywords: B cell subsets; Liver cancer; prognosis; tumor microenvironment (TME); tyramide signal amplification (TSA).

Publication types

  • Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by the Strategic Priority Research Program (No. XDB29030302), Interdisciplinary Innovation Team, Frontier Science Key Research Project (No. QYZDB-SSW-SMC036), Chinese Academy of Sciences; National Key Basic Research Program of China (Nos. 2014CB541904, 2015CB856000) and the National Natural Science Foundation of China (Nos, 31270961, 31470879, 81861138010, 81522036, 81872321, and 81802302).