Adhesion of tumour-infiltrating lymphocytes to endothelium: a phenotypic and functional analysis

Abstract

Summary Efficacy of cancer immunotherapy with cultured tumour-infiltrating lymphocytes (TlLs) depends upon infused TILs migrating into tumour-bearing tissue, in which they mediate an anti-tumour response. For TILs to enter a tumour, they must first bind to tumour endothelium, and this process depends on TILs expressing and regulating the function of relevant cell-surface receptors. We analysed the cell-surface phenotype and endothelial binding of TILs cultured from human melanoma and compared them with peripheral blood T cells and with allostimulated T cells cultured under similar conditions. Compared with peripheral blood T cells, TILs expressed high levels of five integrins, two other adhesion molecules, including the skin homing molecule CLA, and several activation markers and showed markedly enhanced integrin-mediated adhesion to a dermal microvascular endothelial cell line in vitro. Compared with the allostimulated T cells, TILs expressed higher levels of the cutaneous lymphocyte antigen (CLA), the adhesion molecule CD31 and the activation markers CD30 and CD69, but lower levels of several other adhesion and activation molecules. These phenotypic and functional properties of TILs should have complex effects on their migration in vivo. Expression of CLA, the skin homing receptor, may increase migration to melanoma (a skin cancer), whereas integrin activation may cause non-specific binding of TILs to other endothelium. Manipulation of the culture conditions in which TILs are expanded might result in a phenotype that is more conducive to selective tumour homing in vivo.

Vitronectin in human hepatic tumours contributes to the recruitment of lymphocytes in an αvβ3-independent manner

“…The molecule was appropriately expressed on an endothelial cell line. Lack of expression on TIL is consistent with our previous published work showing a lack of avb3 on TIL isolated from malignant melanoma (Adams et al, 1997). Other integrins that can bind vitronectin are not found at high levels on lymphocytes (Nejjari et al, 2002), but the uPAR, which can either modulate the function of other integrins or act directly as an adhesion receptor for vitronectin has been demonstrated on activated lymphocytes and reported to mediate migration (Nykjaer et al, 1994;Wei et al, 1994;Bianchi et al, 1996;Blasi, 1997).…”

“…FACS was used to phenotype TIL, PBL and the dermal microvascular endothelial cell line HMEC-1 (a gift of Dr E Ades (CDC Atlanta, GA, USA)) (Adams et al, 1997). HMEC-1 were grown as described before.…”

Expression and function of CXC and CC chemokines in human malignant liver tumors: A role for human monokine induced by ?-interferon in lymphocyte recruitment to hepatocellular carcinoma

“…6 However, such treatments are only successful if infused lymphocytes are recruited to and retained within the tumor. 6,22,61 The importance of local chemokines in antitumor immune responses is confirmed by studies that show increased T-cell responses against tumor cells transfected with genes for lymphocyte chemokines. 62 We have shown previously that HCC, but not colorectal hepatic metastases, contain the appropriate endothelial adhesion molecules to support lymphocyte recruitment, 10 HEPATOLOGY Vol.…”

“…16,21 Thus, lymphocytes will only be recruited to tissue if they express the appropriate receptors that allow them to respond to locally presented chemokines within tissue. 14 Because lymphocyte adhesion to tumor endothelium appears to be regulated by similar mechanisms, 20,22 it is likely that chemokine/chemokine receptor interactions will also be crucial for the recruitment of lymphocytes to tumors.…”

IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock

“…The binding molecules for ICAM-1 in neutrophils and monocytes are the integrin ligands LFA-1 and Mac-1 [40]. De novo expression of ICAM-1 has been described on different cell types in inflammatory lesion during rejection, and on melanoma cells [41]. Experimental studies have also shown that antibodies against ICAM-1 inhibit leukocyte adhesion to endothelial cells, granulocyte migration through endothelium, and mixed lymphocyte reactions in vitro [42].…”