Subsequently, in response to an antigenic challenge, B cells are clonally expanded and diversify further in a process known as affinity maturation, which includes somatic hypermutation (SHM), followed by clonal selection for B cells that encode productive high-affinity antibodies ( 24). Initially, B cells in the bone marrow are subjected to a V(D)J chromosomal rearrangement process, followed by N/P non-templated nucleotide deletion/insertion ( 23). This technology, coupled with the development of advance computational tools, has enabled the elucidation of the enormous antibody diversity, which, in turn, provides important information about the nature of the B cell response following a challenge ( 22).īCR-Seq enables the exploration of antibody repertoire measures that are associated with the unique diversification mechanisms that B cells undergo during their development. The analysis of antibodies that become anchored to the membrane of the B cell as B cell receptors (BCRs) was made possible by virtue of advances in the next-generation sequencing (NGS) of BCRs (BCR-Seq), which has revolutionized our understanding of B-cell-mediated immunity. These contradictory pieces of evidence have led cancer scientists to hold differing views about whether immunotherapies should be aimed to enhance or inhibit the activity of the B cells in the TME. The above research notwithstanding, reports describing TIL-B activity in cancer remain contradictory, with some studies claiming TIL-B activity to be immunosuppressive ( 16– 18) and others assigning protective roles to these cells ( 19– 21). These data thus demonstrate a possible regulatory role for B cells in the TME ( 15). It has been reported, for example, that the frequency of interleukin (IL)-10-producing B cells in the TME of some cancer types is negatively correlated with that of interferon (IFN)- γ-producing CD8 + T cells but positively correlated with that of regulatory Foxp3 + CD4 + T cells. The discovery of regulatory B cells that secrete cytokines suggests an additional possible role of B cells in the TME ( 13, 14). Of particular importance, TIL-Bs can exhibit direct cytotoxic activity, killing tumor cells via the Fas/FasL pathway ( 11): Activated B cells in tumor-draining lymph nodes (DLNs) have been shown to express the Fas ligand, to be upregulated upon engagement with cells of the 4T1 triple-negative breast cancer (TNBC) cell line, and, in turn, to exhibit cytotoxic activity ( 12). TIL-Bs can also function as antigen-presenting cells that trigger an anti-tumor T cell response ( 9, 10). Among these functions, they can serve as antibody-secreting cells, namely, as plasma cells producing antibodies that inhibit tumor growth by targeting tumor-associated antigens (TAAs) and inducing antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity ( 8). Several possible functions have been attributed to TIL-Bs. Moreover, several reports have described tertiary lymphoid structures (TLS) that contain a relatively high portion of TIL-Bs ( 5– 7). Indeed, it has been reported that tumor-infiltrating lymphocyte B cells (TIL-Bs) can reach up to 40% of all TILs in different types of cancer ( 3, 4). Recent studies have, however, revealed that B cells may play a crucial role in tumor immunity, as these cells consistently comprise a substantial cellular component of the TME. ![]() ![]() For more than two decades, research on the immune response to tumors has focused mainly on T cells, with B cells being under investigated and their roles in the tumor microenvironment (TME) remaining controversial ( 1, 2). The data thus suggests that antibody repertoire signatures can serve as indicators for identifying tumor-reactive B cells.ī cells and T cells are distinct effector cells in the adaptive arm of the immune system yet, they often act in synergy to eradicate pathological processes. Tracing the distribution of TIL-B clones across various compartments indicated that they migrate to and from the TME. Importantly, TIL-Bs were highly mutated but non-class switched, suggesting that class-switch recombination may be inhibited in the TME. We found that TIL-Bs exhibit distinct antibody repertoire measures, including high clonal polarization and elevated somatic hypermutation rates, suggesting a local antigen-driven B-cell response. Here, we utilized B cell receptor high-throughput sequencing (BCR-Seq) to profile the antibody repertoire signature of tumor-infiltrating lymphocyte B cells (TIL−Bs) in comparison to B cells from three anatomic compartments in a mouse model of triple-negative breast cancer. The role of B cells in the tumor microenvironment (TME) has largely been under investigated, and data regarding the antibody repertoire encoded by B cells in the TME and the adjacent lymphoid organs are scarce.
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