title: Anti-CD20 therapy induces a memory Th1 response through the IFN-γ/IL-12 axis and prevents protumor regulatory T-cell expansion in mice.
abstract: The long-lasting clinical response by lymphoma patients to anti-CD20 therapy has been attributed to the induction of an anti-tumor adaptive immunity. We previously demonstrated that a CD4-dependent mechanism is responsible for the long-term protection of CD20(+) tumor-bearing mice by anti-CD20 treatment. Here, we compare tumor immunity in tumor-bearing animals that did or did not receive anti-CD20 treatment. Splenic CD4(+)FoxP3(+) regulatory T cells (Tregs) expanded substantially in untreated mice that exhibited then a reduced survival, whereas Tregs depletion led to long-term survival of the animals, suggesting the establishment of a Treg-dependent immunosuppressive environment after tumor injection. Strikingly, anti-CD20 therapy reversed the initial expansion of Tregs, and was accompanied by a marked increase in the number of Th1 cells, with no detectable change in Th2 and Th17 cell numbers. Interleukin-12 serum level was also increased by the anti-CD20 treatment, and activated myeloid dendritic cells producing interleukin-12 could be detected in lymph nodes of treated animals, while interferon-γ blockade strongly reduced survival. Also, CD4(+) effector memory T cells were evidenced in surviving animals, and the transfer of CD4(+) T cells induced long-term protection. Thus, anti-CD20 therapy promotes strong anti-tumor adaptive immunity, opposes Treg expansion and inhibits tumor cells from maintaining an immunosuppressive environment.
authors.affiliation: 1] Cordeliers Research Center-INSERM UMR-S 1138, Paris, France [2] Paris Descartes-Paris 5 University, UMR-S 1138, Paris, France [3] Pierre et Marie Curie-Paris 6 University, UMR-S 1138, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Deligne
authors.affiliation: 1] Cordeliers Research Center-INSERM UMR-S 1138, Paris, France [2] Pierre et Marie Curie-Paris 6 University, UMR-S 1138, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Metidji
authors.affiliation: 1] Cordeliers Research Center-INSERM UMR-S 1138, Paris, France [2] Paris Descartes-Paris 5 University, UMR-S 1138, Paris, France [3] Pierre et Marie Curie-Paris 6 University, UMR-S 1138, Paris, France.
authors.forename: W-H
authors.initials: WH
authors.lastname: Fridman
authors.affiliation: 1] Cordeliers Research Center-INSERM UMR-S 1138, Paris, France [2] Paris Descartes-Paris 5 University, UMR-S 1138, Paris, France [3] Pierre et Marie Curie-Paris 6 University, UMR-S 1138, Paris, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Teillaud
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000069283:Rituximab; D015398:Signal Transduction; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018664:Interleukin-12; D000069283:Rituximab; D007371:Interferon-gamma