Tertiary lymphoid structures and B cells: An intratumoral immunity cycle.

The generation of anti-tumor immunity in the draining lymph nodes is known as the cancer immunity cycle. Accumulating evidence supports the occurrence of such a cycle at tumor sites in the context of chronic inflammation. Here, we review the role of tertiary lymphoid structures (TLS) in the generation of T and B cell immunities, focusing on the impact of B cells that undergo full maturation, resulting in the generation of plasma cells (PCs) producing high-affinity IgG and IgA antibodies. In this context, we propose that antibodies binding to tumor cells induce macrophage or natural killer (NK)-cell-dependent apoptosis. Subsequently, released antigen-antibody complexes are internalized and processed by dendritic cells (DCs), amplifying antigen presentation to T cells. Immune complexes may also be fixed by follicular DCs (FDCs) in TLS, thereby increasing memory B cell responses. This amplification loop creates an intra-tumoral immunity cycle, capable of increasing sensitivity of tumors to immunotherapy even in cancers with low mutational burden.

Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma 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.