Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy.
Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non-CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy.
Thanarajasingam
Uma
U
Molecular Medicine Program and Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA.
Sanz
Laura
L
Diaz
Rosa
R
Qiao
Jian
J
Sanchez-Perez
Luis
L
Kottke
Tim
T
Thompson
Jill
J
Chester
John
J
Vile
Richard G
RG
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019041:L-Selectin / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D000951:Antigens, Neoplasm; C515480:Ccl21a protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D019041:L-Selectin