Antitumor Plasma Cells Mature Within Tertiary Lymphoid Structures

Defined as lymphoid aggregates that develop in nonlymphoid tissues, tertiary lymphoid structures (TLS) can be found within the tumor microenvironment and are associated with improved clinical outcomes in multiple cancer types. Consisting of dendritic, T, and B cells, TLSs can serve as sites of immune activation and also harbor germinal centers, which promote maturation of B cells into antibody-secreting plasma cells (PC). To investigate how B cells and PCs may impact the antitumor response, Meylan and colleagues studied the features of intratumoral TLSs in tumor samples from patients with clear-cell renal cell carcinoma (ccRCC). Spatial transcriptomic analyses of TLS⁺ and TLS^– tumor tissue suggested an association of TLS areas with a gene signature corresponding to the B lineage, which includes the maturation stages between immature B cells and terminally differentiated PCs, as well as T-cell and fibroblast gene signatures. Comparison of TLS areas with surrounding tumor tissue enabled creation of a 29-gene TLS imprint signature, including immunoglobulin genes such as IGHA1 and IGHG1, B-cell markers including MZB1, and fibroblast markers like CXCL12. Supporting the concept of intratumoral in situ B-cell maturation toward PCs, spatial B-cell receptor profiling analysis revealed evidence of somatic hypermutation and clonal selection, with colocalization analyses indicating the presence of IgG- and IgA-expressing PCs within TLSs as well as the dissemination into tumors upon a network of CXCL12⁺ fibroblasts. Antibody-producing PCs densely surrounded tumor cells strongly labeled with IgG, highlighting antibody-dependent cellular cytotoxicity (ADCC) as a potential PC-mediated antitumor response. Accordingly, in samples with abundant IgG tumoral staining and a robust amount of apoptotic tumor cells, CD68⁺ macrophages, one of the main effectors of ADCC, were correlated with cleaved caspase 3⁺ (a marker of apoptosis) tumor cells. Notably, there was also a positive correlation between high tumoral IgG staining and response to immune checkpoint inhibitors in patients with ccRCC. In summary, this study indicates the importance of intratumoral PC maturation in an antibody-mediated antitumor response and supports its association with immunotherapy outcomes.

Meylan M, Petitprez F, Becht E, Bougoüin A, Pupier G, Calvez A, et al. Tertiary lymphoid structures generate and propagate anti-tumor 
antibody-producing plasma cells in renal cell cancer. Immunity 2022;
55:527–41.e5.

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