Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses.
OBJECTIVE
One of the most important rate-limiting steps in adoptive cell transfer (ACT) is the inefficient migration of T cells to tumors. Because melanomas specifically express the chemokines CXCL1 and CXCL8 that are known to facilitate the CXCR2-dependent migration by monocytes, our aim is to evaluate whether introduction of the CXCR2 gene into tumor-specific T cells could further improve the effectiveness of ACT by enhancing T-cell migration to tumor.


METHODS
In this study, we used transgenic pmel-1 T cells, which recognize gp100 in the context of H-2Db, that were transduced with luciferase gene to monitor the migration of transferred T cells in vivo. To visualize luciferase-expressing T cells within a tumor, a nonpigmented tumor is required. Therefore, we used the MC38 tumor model, which naturally expresses CXCL1.


RESULTS
Mice bearing MC38/gp100 tumor cells treated with CXCR2/luciferase-transduced pmel-1 T cells showed enhanced tumor regression and survival compared with mice receiving control luciferase-transduced pmel-1 T cells. We also observed preferential accumulation of CXCR2-expressing pmel-1 T cells in the tumor sites of these mice using bioluminescence imaging. A similar enhancement in tumor regression and survival was observed when CXCR2-transduced pmel-1 T cells were transferred into mice bearing CXCL1-transduced B16 tumors compared with mice treated with control pmel-1 T cells.


CONCLUSIONS
These results implicate that the introduction of the CXCR2 gene into tumor-specific T cells can enhance their localization to tumors and improve antitumor immune responses. This strategy may ultimately enable personalization of cancer therapies based on chemokine expression by tumors.
Peng
Weiyi
W
Departments of Melanoma Medical Oncology and Experimental Diagnostic Imaging, The Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Ye
Yang
Y
Rabinovich
Brian A
BA
Liu
Chengwen
C
Lou
Yanyan
Y
Zhang
Minying
M
Whittington
Mayra
M
Yang
Yan
Y
Overwijk
Willem W
WW
Lizée
Gregory
G
Hwu
Patrick
P
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D023063:Receptors, Interleukin-8B; D008156:Luciferases