Immunological potential of tertiary lymphoid structures surrounding the primary tumor in gastric cancer

Abstract

Tertiary lymphoid structures (TLSs), which consist of B cells, T cells, follicular dendritic cells and high endothelial venules, have recently been found to be associated with effective antitumor immune responses in patients with cancer. Tumor-infiltrating T cells and B cells have each been demonstrated to be associated with survival in patients with cancer. We hypothesized that TLSs, an assembly of immune cells, may be important for the initiation and/or maintenance of T cell and B cell responses against tumors. The aim of the present study was to examine the cellular mechanism of B cells in TLSs within gastric cancer and to understand the antitumor immune response of TLSs. Each B cell subset in a tumor was examined using flow cytometry to evaluate B cell differentiation and the functional status of B cells. In addition, B cell clonality was investigated by analyzing the B cell antigen receptor gene using PCR, and the function and formation/maintenance of TLSs were evaluated using reverse transcription-quantitative PCR. Tumor-infiltrating B cells were more differentiated compared with that in distant non-tumor tissues and tumor-draining lymph nodes. The PCR results revealed specific BCR gene expression in tumor-infiltrating B cells. The expression of co-stimulatory factors, CD80 and CD86, was observed, in addition to the constantly expressed major histocompatibility complex molecules (HLA-ABC and HLA-DR). CD70 was expressed in addition to CD27 in both CD20 + B cells and CD8 + T cells, indicating that these factors are activated together through their interaction. The mRNA expression levels of CCL21, CXCL13, PD-L1, perforin and granzyme B in TLSs was significantly higher compared with that in non-TLSs. The majority of tumor-infiltrating B cells in gastric cancer exist in the form of TLSs around the tumor and have been antigen-sensitized and differentiated, and proliferated in TLSs but not in the lymph nodes. In addition, B cells in TLSs might primarily function as antigen-presenting cells and be associated with the induction of cytotoxic T cells.

Tertiary lymphoid structures and B lymphocytes in cancer prognosis and response to immunotherapies

“…In addition, other gene signatures containing 8 and 19 genes related to the presence of T follicular helper cells, type 1 helper CD4 + T cells and B cells were reported in breast 54 and gastric 55 cancers. Collectively, this has led to the detection of TLS in lung, 41 , 45 , 56 , 57 oral squamous cell carcinoma, 58 breast, 54 , 59–61 colon, 51 , 62 stomach, 55 , 63 , 64 liver, 65 sarcoma, 3 , 66 , 67 bladder, 68 clear cell renal cell carcinoma, 4 ovarian cancer 46 , 69 and melanoma 4 , 5 , 15 , 44 , 50 , 70 ( Table 1 ). TLS formation and densities vary between tumor types, and between patients.…”

“… Favorable N.A. 64 Liver Hepatocellular carcinoma Primary tumors Naive Tumor Hematein-eosin-saffron stained slides and genes signature Presence of intr-tumoral TLS associated with a lower risk of early relapse N.A. 65 Sarcoma Six different histology types (DDLPS, LMS, UPS, Synovial sarcoma, Myxoid liposarcoma and GIST) Primary tumors N.A.…”

“…They also secrete IFN-γ, which drives Th1 and cytotoxic response by polarizing macrophages, CD4 + and CD8 + T cells ( Figure 3 ). Hence, IgG + ASCs and memory B cells make a valuable contribution to the antitumor response, and their presence is positively correlated to increased survival in patients with high-grade serious ovarian cancer, 46 , 114 hepatocellular carcinoma, 93 melanoma, 105 , 123 KRAS-mutant lung carcinoma, 103 pancreatic, 124 , 125 gastric, 64 , 126 breast 80 , 113 , 127 and non-small cell lung cancers. 96 , 103

Figure 3.

…”

Cutaneous Melanoma: Mutational Status and Potential Links to Tertiary Lymphoid Structure Formation

“…TLS consist of organized aggregates of T cells, B cells, dendritic cells (DC), follicular dendritic cells (FDC), T follicular helper (Tfh) cells, specialized stromal fibroblasts, and high endothelial venules (HEV) ( 20 , 21 ). When compared with SLO, TLS are non-encapsulated which is thought to facilitate rapid antigen presentation at the site of inflammation and, in the context of cancer, allows the locally primed immune system to quickly mediate surveillance of cognate tumor-associated (neo)antigens ( 18 ).…”

CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

“…They also regulate various cancer functions including progression, metastasis, apoptosis, and chemoresistance [ 10 , 11 , 12 ]. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a vital role in the development of several cancers (e.g., gastric, colorectal, breast and lung cancers), the promotion of angiogenesis, and the metastatic cascade [ 13 , 14 , 15 , 16 ]. Elevated levels of CXCL13 and its cognate receptor, CXCR5, are found in many types of cancer cells [ 16 ].…”