B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies

Abstract

Baildon (2019) B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies, OncoImmunology, 8:1, e1512458, ABSTRACT Tumor-infiltrating lymphocytes (TILs) are correlated to prognosis of several kinds of cancer. Most studies focused on T cells, while the role of tumor-associated B cells (TABs) has only recently gained more attention. TABs contain subpopulations with distinct functions, potentially promoting or inhibiting immune responses. This study provides a detailed analysis of TABs in gastro-esophageal adenocarcinoma (EAC). Flow cytometric analyses of single cell suspensions of tumor samples, mucosa, lymph nodes and peripheral blood mononuclear cells (PBMC) of EAC patients and healthy controls revealed a distinct B cell compartment in cancer patients. B cells were increased in tumor samples and subset-analyses of TILs showed increased proportions of differentiated and activated B cells and an enrichment for follicular T helper cells. Confocal microscopy demonstrated that TABs were mainly organized in tertiary lymphoid structures (TLS), which resemble lymphoid follicles in secondary lymphoid organs. A panel of 34 tumorassociated antigens (TAAs) expressed in EAC was identified based on public databases and TCGA data to analyze tumor-specific B cell responses using a LUMINEX TM bead assay and flow cytometry. Structural analyses of TLS and the detection of tumor-specific antibodies against one or more TAAs in 48.1% of analyzed serum samples underline presence of anti-tumor B cell responses in EAC. Interestingly, B cells were decreased in tumors with expression of Programmed Death Ligand 1 or impaired HLA-I expression. These data demonstrate that anti-tumor B cell responses are an additional and underestimated aspect of EAC. Our results are of immediate translational relevance to emerging immunotherapies. ARTICLE HISTORY

Tertiary lymphoid structures in the era of cancer immunotherapy

“…Il-17R, IL-17 receptor. has also been described in NSCLC, ovarian cancer and gastric-oesophageal adenocarcinoma 20,38,48,69 . Altogether, these studies demonstrate that TLSs enable the generation of effector and memory B cell responses against tumour antigens, leading to antibody production.…”

“…Expression of AID and BCL-6 necessary for the generation of somatic hypermutations and the activation of isotypic switch machineries is detected in TLS B cells, leading to the generation of effector B cells differentiating into plasma cells and of memory B cells sustaining a long-term immune response 20,38,60,62 . Analysis of the repertoire of rearranged immunoglobulin genes in the B cells of microdissected follicles, compared with peripheral B cells, revealed clonal amplification, indicating a local antigen-driven B cell response in cutaneous melanoma metastases 58 , omental metastases of ovarian cancer 38,48 , gastric-oesophageal adenocarcinoma 69 and invasive breast ductal carcinoma 70,71 . Chemoattractant CXCL13producing PD1 + T FH cells known to help facilitate B cell responses were detected close to TLS B cells in breast cancer and in soft tissue sarcoma 39,72 .…”

Tumor-infiltrating B cells signal functional humoral immune responses in breast cancer

“…We further identified 8 antigens that elicit BC-associated autoantibody responses (39). In esophago-gastric adenocarcinoma, 48% of plasma samples were positive for 1 or more TAA (40). The ability of TIL-B to present antigen to CD4 + TIL has also been demonstrated to function in NSCLC and alter the CD4 + TIL phenotype (41).…”

Duality of B Cell-CXCL13 Axis in Tumor Immunology

“…The contribution of B cells in tumor immunity remains controversial. However, there is consensus on their importance for generating antibodies which bind to specific antigen epitopes and label them for degradation or targeting (16). B cells function as APCs by utilizing their B cell receptor (BCR) to recognize antigens and are important for presenting foreign and autoantigens to CD4+ T cells (17)(18)(19).…”