TY - JOUR
T1 - Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2
AU - Kershaw, Michael H.
AU - Wang, Gang
AU - Westwood, Jennifer A.
AU - Pachynski, Russell K.
AU - Tiffany, H. Lee
AU - Marincola, Francesco M.
AU - Wang, Ena
AU - Young, Howard A.
AU - Murphy, Philip M.
AU - Hwu, Patrick
PY - 2002/11/1
Y1 - 2002/11/1
N2 - T-cell-based immunotherapies provide a promising means of cancer treatment although durable antitumor responses are infrequent. A potential reason for these shortcomings may lie in the observed lack of trafficking of specific T cells to tumor. Our increasing knowledge of the process of trafficking involving adhesion molecules and chemokines affords us the opportunity to intervene and correct deficiencies in this process. Chemokines can be expressed by a range of tumors and may serve as suitable targets for directing specific T cells toward tumor. We initially sought to identify which chemokines were produced by a range of human tumor cell lines, and which chemokines and chemokine receptors were expressed by cultured T cells. We identified two chemokines: Growth-Regulated Oncogene-α (Gro-α; CXCL1) and Regulated on Activation Normal T Cell-Expressed and Secreted (RANTES; CCL5), to be secreted by several human tumor cell lines. Expression was also detected in fine-needle aspirates of melanoma from patients. In addition, we determined the expression of several chemokine receptors on cultured human T cells including CCR1, CCR2, CCR4, CCR5, CXCR3, and CXCR4. Cultured, activated human T cells expressed the chemokines lymphotactin (XCL1), RANTES, macrophage inflammatory protein-1α (MIP-1α; CCL3) and MIP-1β (CCL4), but no appreciable Gro-α. In a strategy to direct T cells toward chemokines expressed by tumors we chose Gro-α as the target chemokine because it was produced by tumor and not by T cells themselves. However, T cells did not express the receptor for Gro-α, CXCR2, and therefore, T cells were transduced with a retroviral vector encoding CXCR2. Calcium ion mobilization, an important first step in chemokine receptor signaling, was subsequently demonstrated in transduced T cells in response to Gro-α. In addition, Gro-α was chemotactic for T cells expressing CXCR2 in vitro toward both recombinant protein and tumor-derived chemokine. Interestingly we demonstrate, for the first time, that Gro-α was able to induce interferon-γ (IFN-γ) secretion from transduced T cells, thereby extending our knowledge of other potential functions of CXCR2. This study demonstrates the feasibility of redirecting the migration properties of T cells toward chemokines secreted by tumors.
AB - T-cell-based immunotherapies provide a promising means of cancer treatment although durable antitumor responses are infrequent. A potential reason for these shortcomings may lie in the observed lack of trafficking of specific T cells to tumor. Our increasing knowledge of the process of trafficking involving adhesion molecules and chemokines affords us the opportunity to intervene and correct deficiencies in this process. Chemokines can be expressed by a range of tumors and may serve as suitable targets for directing specific T cells toward tumor. We initially sought to identify which chemokines were produced by a range of human tumor cell lines, and which chemokines and chemokine receptors were expressed by cultured T cells. We identified two chemokines: Growth-Regulated Oncogene-α (Gro-α; CXCL1) and Regulated on Activation Normal T Cell-Expressed and Secreted (RANTES; CCL5), to be secreted by several human tumor cell lines. Expression was also detected in fine-needle aspirates of melanoma from patients. In addition, we determined the expression of several chemokine receptors on cultured human T cells including CCR1, CCR2, CCR4, CCR5, CXCR3, and CXCR4. Cultured, activated human T cells expressed the chemokines lymphotactin (XCL1), RANTES, macrophage inflammatory protein-1α (MIP-1α; CCL3) and MIP-1β (CCL4), but no appreciable Gro-α. In a strategy to direct T cells toward chemokines expressed by tumors we chose Gro-α as the target chemokine because it was produced by tumor and not by T cells themselves. However, T cells did not express the receptor for Gro-α, CXCR2, and therefore, T cells were transduced with a retroviral vector encoding CXCR2. Calcium ion mobilization, an important first step in chemokine receptor signaling, was subsequently demonstrated in transduced T cells in response to Gro-α. In addition, Gro-α was chemotactic for T cells expressing CXCR2 in vitro toward both recombinant protein and tumor-derived chemokine. Interestingly we demonstrate, for the first time, that Gro-α was able to induce interferon-γ (IFN-γ) secretion from transduced T cells, thereby extending our knowledge of other potential functions of CXCR2. This study demonstrates the feasibility of redirecting the migration properties of T cells toward chemokines secreted by tumors.
UR - http://www.scopus.com/inward/record.url?scp=0036428790&partnerID=8YFLogxK
U2 - 10.1089/10430340260355374
DO - 10.1089/10430340260355374
M3 - Article
C2 - 12427307
AN - SCOPUS:0036428790
SN - 1043-0342
VL - 13
SP - 1971
EP - 1980
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 16
ER -