Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing cells in renal cell cancer

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG-and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

Automated summary

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in renal cell carcinoma (RCC). B cells are enriched in TLS and demonstrate diverse maturation stages, with the presence of fully mature clonotypes. Additionally, IgG-and IgA-producing plasma cells (PCs) disseminate into the tumor beds along fibroblastic tracks in TLS+ tumors, indicating potential anti-tumor effector activity. Furthermore, the presence of IgG-stained tumor cells correlates with therapeutic responses and progression-free survival in RCC patients treated with immune checkpoint inhibitors.