Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3⁺ T cells in lymphocyte‐rich gastric carcinoma

Abstract

The neoplastic environment is generally regarded as an immunosuppressive milieu. However, a group of cancers are characterized by the abundance of tumour-infiltrating lymphocytes (TILs). Here we examined the possible roles of chemokines in the formation of lymphoid stroma in lymphocyte-rich gastric carcinomas (GCs), including EBV(+) cases and conventional GCs. Regardless of EBV positivity, TILs in lymphocyte-rich GCs predominantly expressed CXCR3, while its ligand CXCL9 was abundantly expressed by stromal cells and a portion of cancer cells. CXCL9(+) stromal cells were judged to include dendritic cells, because they partly co-expressed fascin, DC-sign, CD83, DC-lamp or HLA-DR. T cells in close contact with CXCL9(+) cells showed frequent labelling of Ki-67 (approximately 10%), suggesting the immunostimulatory activity of CXCL9(+) stromal cells. The T-cell zone of the regional lymph nodes of lymphocyte-rich GCs also abounded with CXCR3(+) T cells and CXCL9(+) stromal cells. This indicated a close similarity between cancer stroma and regional lymph nodes of lymphocyte-rich GCs. Quantitative RT-PCR also confirmed the strong expression of CXCR3, CXCL9 and IFNgamma in lymphocyte-rich GCs. In contrast, conventional GCs contained less abundant CXCR3(+) T cells and few CXCL9(+) stromal cells. Collectively, the CXCL9-CXCR3 axis plays a pivotal role in the formation of lymphoid stroma in lymphocyte-rich GCs. Given similar findings in the regional lymph nodes, the lymphoid stroma of lymphocyte-rich GCs may represent a tertiary lymphoid tissue with predominantly Th1-shifted immune responses.

Chemokines in cancer related inflammation

“…TIL have been reported to express the CXCR3 receptor; the corresponding ligands CXCL9 and CXCL10 can elicit anti-tumoral responses which correlated with increased infiltration of CD4 and CD8 lymphocytes [48]. In gastric and colorectal carcinoma [49,50] significant levels of CXCL9 and CXCL10 are produced by stromal cells, and are correlated with CXCR3-positive TIL. Murine tumors engineered with CXCL9 or CXCL10 [51,52], and intra-tumor injection of CXCL9 [48] further demonstrated the ability of these chemokines to recruit T as well as NK cells and to elicit antitumoral responses.…”

Prolonged Antitumor NK Cell Reactivity Elicited by CXCL10-Expressing Dendritic Cells Licensed by CD40L+CD4+ Memory T Cells

“…Splenic DCs were isolated using CD11c-MACS beads from collagenase-treated spleens of naive B6 or BALB/c mice. 51 Cr release assays were performed for evaluation of cytotoxic activity of NK cells. Briefly, target cells were labeled with Na 2 51 CrO 4 (0.1 Ci/10 6 cells) for 1 h at 37˚C.…”

Immune Cell Responses in Gastric Carcinoma

“…The author has designated this type of distribution "CXCR3 + T cell-CXCL9 + stromal cell clustering", which is clearly observed by double staining (Fig. 4E) (Ohtani et al 2009(Ohtani et al , 2010. At higher magnification, a close cell-to-cell contact between CXCL9 + stromal cells and CXCR3 + cells is revealed (Fig.…”

“…Lymphoid tissues newly formed in the peripheral tissues during chronic inflammation are designated "tertiary lymphoid tissues" (Aloisi et al 2006). The author proposes, therefore, that lymphoid stroma in lymphocyte-rich gastric cancer can be regarded as tertiary lymphoid tissue (Ohtani et al 2009). Hence, immunostimulatory aspects of lymphocyte-rich gastric cancers have been clarified in this chapter.…”

“…Chemokines and their receptors play important roles in inflammation, lymphoid organogenesis and cancer cell invasion and/or metastasis. The chemokine receptor CXCR3 and two of its cognate ligands, CXCL9 (MIG) and CXCL10 (IP10) are described here because CXCR3 is widely expressed by T helper type 1 (Th1) cells and CD8 + T cells (Zlotnik and Yoshie, 2000;Ohtani et al 2009). By immunohistochemistry, CXCR3 + lymphocytes are abundant in the lymphoid stroma of lymphocyte-rich gastric cancers (Fig.…”