Tumor infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T cell responses, and superior prognosis in ovarian cancer

Purpose: CD8+ tumor-infiltrating lymphoyctes (TIL) are key mediators of anti-tumor immunity and are strongly associated with survival in virtually all solid tumors. However, the prognostic effect of CD8+ TIL is markedly higher in the presence of CD20+ B cells, suggesting cooperative interactions between these lymphocyte subsets lead to more potent anti-tumor immunity. Experimental Design: We assessed the co-localization patterns, phenotypes, and gene expression profiles of tumor-associated T- and B-lineage cells in high grade serous ovarian cancer (HGSC) by multicolor immunohistochemistry, flow cytometry, and bioinformatic analysis of gene expression data from The Cancer Genome Atlas. Results: T cells and B cells co-localized in four types of lymphoid aggregate, ranging from small, diffuse clusters to large, well-organized tertiary lymphoid structures (TLS) resembling activated lymph nodes. TLS were frequently surrounded by dense infiltrates of plasma cells (PCs), which comprised up to 90% of tumor stroma. PCs expressed mature, oligoclonal immunoglobulin G transcripts, indicative of antigen-specific responses. PCs were associated with the highest levels of CD8+, CD4+ and CD20+ TIL, as well as numerous cytotoxicity-related gene products. CD8+ TIL carried prognostic benefit only in the presence of PCs and these other TIL subsets. PCs were independent of mutation load, BRCA1/2 status, and differentiation antigens but positively associated with cancer-testis antigens. Conclusions: PCs are associated with the most robust, prognostically favorable CD8+ TIL responses in HGSC. We propose that TLS facilitate coordinated anti-tumor responses involving the combined actions of cytolytic T cells and antibody-producing PCs.

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