Transduction of Tumor-Specific T Cells with CXCR2 Chemokine Receptor Improves Migration to Tumor and Antitumor Immune Responses

Abstract

Purpose One of the most important rate-limiting steps in adoptive cell transfer (ACT) is the inefficient migration of T cells to tumors. Since 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. Experimental Design In this study, we utilized 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. In order to visualize luciferase-expressing T cells within a tumor, a non-pigmented tumor is required. Therefore, we utilized 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 to 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 to 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.

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…34 A strategy the same group later pursued in a genetically modified B16 mouse model of homing of T cells, engineered to express murine CXCR2, towards murine CXCL1. 35 We are the first to show, that transduction with human CXCR2 significantly increases homing and infiltration of human T cells into s.c. human tumors in a xenograft model of melanoma.…”

“…CCR2, 40 CXCR1, 30 CXCR2 34 , 35 and CXCR3 41 transduction of T and NK cells have been pursued in pre-clinical models, showing increased homing to tumor site, and as a result improved tumor control, setting the stage for human trials. A phase I/II study of lymphodepletion plus ACT with CXCR2 and Nerve Growth Factor Receptor (NGFR) transduced TILs are currently being investigated in patients with MM (NCT01740557).…”

The progress of immunotherapy for glioblastoma

“…By such means of genetically modifying T cells and prolonging their survival time, the effect of specific T cells could be enhanced. [23][24] Additionally, the reinfusion of the T cells proliferated in vitro back into the body can correct lymphopenia and improve immunosuppressive environment, [25][26] thereby enhancing tumor immunity.…”

CCL21 modulates the migration of NSCL cancer by changing the concentration of intracellular Ca2+

“…It has been demonstrated that chemokines and their receptors play a key role in the recruitment of leukocytes to the site of inflammation. Recent studies have shown that they are also correlated to tumor progression, invasion and metastasis of many other kinds of tumors such as breast cancer (14)(15)(16)(17)(18), gastric cancer, colorectal cancer, pancreatic cancer, lung cancer, oral squamous cell carcinoma, nasopharyngeal carcinoma, prostate cancer and neuroectodermal tumors (19)(20)(21)(22)(23).…”