CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells.
T cell adoptive transfer strategies that have produced clinical remissions against specific tumors have so far produced disappointing results against ovarian cancer. Recent evidence suggests that adoptively transferred CD4(+) T cells can trigger endogenous immune responses in particular patients with ovarian cancer through unknown mechanisms. However, conflicting reports suggest that ovarian cancer-infiltrating CD4(+) T cells are associated with negative outcomes. In this study, we elucidate the phenotypic attributes that enable polyclonal CD4(+) T cells briefly primed against tumor Ags to induce therapeutically relevant endogenous antitumor immune responses. Our results unveil a therapeutic mechanism whereby tumor-primed CD4(+) T cells transferred into ovarian cancer-bearing mice secrete high levels of CCL5, which recruits endogenous CCR5(+) dendritic cells to tumor locations and activate them through CD40-CD40L interactions. These newly matured dendritic cells are then able to prime tumor-specific endogenous CD8(+) T cells, which mediate long-term protection. Correspondingly, administration of tumor-primed CD4(+) T cells significantly delayed progression of MHC class II(-) ovarian cancers, similarly to CD8(+) T cells only, and directly activated wild-type but not CD40-deficient dendritic cells recruited to the tumor microenvironment. Our results unveil a CCL5- and CD40L-dependent mechanism of transferring immunity from exogenously activated CD4(+) T cells to tumor-exposed host cells, resulting in sustained antitumor effects. Our data provide a mechanistic rationale for incorporating tumor-reactive CD4(+) T cells in adoptive cell transfer immunotherapies against ovarian cancer and underscore the importance of optimizing immunotherapeutic strategies for the specific microenvironment of individual tumors.
Nesbeth
Yolanda C
YC
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Martinez
Diana G
DG
Toraya
Seiko
S
Scarlett
Uciane K
UK
Cubillos-Ruiz
Juan R
JR
Rutkowski
Melanie R
MR
Conejo-Garcia
Jose R
JR
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018827:Carcinoma, Lewis Lung; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000008:administration & dosage / Q000378:metabolism* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000502:physiology
D019013:CD40 Antigens; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D000949:Histocompatibility Antigens Class II; D019713:Receptors, CCR5; D023201:CD40 Ligand
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