Understanding the biology of ex vivo-expanded CD8 T cells for adoptive cell therapy: role of CD62L.
CD62L governs the circulation of CD8(+) T cells between lymph nodes and peripheral tissues, whereby the expression of CD62L by CD8(+) T cells promotes their recirculation through lymph nodes. As such, CD62L participates in the fate of adoptively transferred CD8(+) T cells and may control their effectiveness for cancer immunotherapy, including settings in which host preconditioning results in the acute lymphopenia-induced proliferation of the transferred cells. Indeed, previous studies correlated CD62L expression by donor CD8(+) cells with the success rate of adoptive cell therapy (ACT). Here, we analyzed the functions and fate of ex vivo-activated, tumor-specific CD62L(-/-) CD8(+) T cells in a mouse melanoma model for ACT. Unexpectedly, we observed that CD62L(-/-) CD8(+) T cells were functionally indistinguishable from CD62L(+/+) CD8(+) T cells, i.e., both greatly expanded in cyclophosphamide preconditioned animals, controlled subcutaneously and hematogenously spreading tumors, and generated anti-tumor-specific CD8(+) T cell memory. Moreover, even in hosts with rudimentary secondary lymphoid organs (LT(-/-) animals), CD8(+) T cells with and without CD62L expanded equivalently to those adoptively transferred into wild-type animals. These results put into question the utility of CD62L as a predictive biomarker for the efficacy of ex vivo-expanded T cells after ACT in lymphopenic conditions and also offer new insights into the homing, engraftment, and memory generation of adoptively transferred ex vivo-activated CD8(+) T cells.
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, diazc2@ccf.org.
C Marcela
CM
Díaz-Montero
Abdel-Aziz
AA
Zidan
Maria F
MF
Pallin
Vasileios
V
Anagnostopoulos
Mohamed L
ML
Salem
Eric
E
Wieder
Krishna
K
Komanduri
Alberto J
AJ
Montero
Mathias G
MG
Lichtenheld
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D007156:Immunologic Memory; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology / Q000628:therapy; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D047368:Tumor Burden / Q000276:immunology; D058951:gp100 Melanoma Antigen / Q000276:immunology / Q000378:metabolism
D058951:gp100 Melanoma Antigen; D019041:L-Selectin