Abstract
Lymphoid neogenesis gives rise to tertiary lymphoid structures (TLS) in the periphery of multiple cancer types including muscle invasive bladder cancer (MIBC) where it has positive prognostic and predictive associations. Here, we explored molecular, clinical, and histological data of The Cancer Genome Atlas, as well as the IMvigor210 dataset to study factors associated with TLS development and function in the tumor microenvironment (TME) of MIBC. We also analyzed tumor immune composition including TLS in an independent, retrospective MIBC cohort. We found that the combination of TLS density and tumor mutational burden provides a novel independent prognostic biomarker in MIBC. Gene expression profiles obtained from intratumoral regions that rarely contain TLS in MIBC showed poor correlation with the prognostic TLS density measured in tumor periphery. Tumors with high TLS density showed increased gene signatures as well as infiltration of activated lymphocytes. Intratumoral B-cell and CD8+ T-cell co-infiltration was frequent in TLS-high samples, and such regions harbored the highest proportion of PD-1+TCF1+ progenitor-like T cells, naïve T cells, and activated B cells when compared to regions predominantly infiltrated by either B cells or CD8+ T cells alone. We found four TLS maturation subtypes; however, differences in TLS composition appeared to be dictated by the TME and not by the TLS maturation status. Finally, we identified one downregulated and three upregulated non-immune cell-related genes in TME with high TLS density, which may represent candidates for tumor-intrinsic regulation of lymphoid neogenesis. Our study provides novel insights into TLS-associated gene expression and immune contexture of MIBC and indicates towards the relevance of B-cell and CD8+ T-cell interactions in anti-tumor immunity within and outside TLS.
Highlights
In chronically inflamed tissues including cancer, infiltrating lymphocytes can form ectopic lymphoid organs termed tertiary lymphoid structures (TLS) via lymphoid neogenesis [1, 2]
We observed that the average size of TLS and germinal center (GC), as well as the density of GC was positively associated with TLS density (Figures 1G, H and Supplementary Figures 6A–D), suggesting that tumor microenvironments where TLS are initiated allow subsequent maturation and generation of GC
We found that d-TLS density determined by histology of diagnostic sections did not correlate with TLS-related gene expression profiles in intratumoral regions obtained from matched cryosamples
Summary
In chronically inflamed tissues including cancer, infiltrating lymphocytes can form ectopic lymphoid organs termed tertiary lymphoid structures (TLS) via lymphoid neogenesis [1, 2]. TLS density in the tumor microenvironment (TME) correlates with increased infiltration of adaptive immune cells and improved patient survival in a growing list of solid tumors [5, 6] including muscle invasive bladder cancer (MIBC) [7]. Similar observations were reported in sarcoma, melanoma, and renal cell carcinoma patients [11,12,13]. This has fueled the hypothesis that TLS are drivers of anti-tumor immunity and that, TLS induction could be considered as a therapeutic strategy [5, 6]
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