Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype.
The functional development of tumor-specific CD4(+) T cells has a critical impact on the outcome of antitumor immune responses. Adoptive immunotherapy involving tumor-specific CD4(+) T cells has shown encouraging clinical benefits in some cancer patients. To mount an effective antitumor immunity, it is desirable to elicit activated type 1 T helper cells. Here, we report that type 1 T helper cell-like effector cells that arose in tumor-bearing hosts progressively expressed programmed death 1 during tumor growth. The programmed death 1(hi) effector cells displayed a dysfunctional phenotype, characterized by selective down-regulation of interleukin-7 receptor, heightened apoptosis, and poor antitumor efficacy. This tumor-driven aberrant T-cell response could be prevented by a single dose of the widely used chemotherapy agent cyclophosphamide. We show that chemotherapy conditioned the host environment, creating a transient window for optimal effector differentiation for adoptively transferred CD4(+) T cells. This robust effector differentiation, which was antigen-driven and mechanistically dependent on an intact host response to type I interferon, gave rise to activated polyfunctional T helper cells with high interleukin-7 receptor, rapid clonal expansion, and potent antitumor activity against established B-cell lymphomas. We hypothesize that prevention of tumor-induced effector cell dysfunction is a major mechanism contributing to the efficacy of combined chemoimmunotherapy.
Ding
Zhi-Chun
ZC
Cancer Immunotherapy Program, MCG Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.
Blazar
Bruce R
BR
Mellor
Andrew L
AL
Munn
David H
DH
Zhou
Gang
G
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016219:Immunotherapy, Adoptive; D007370:Interferon Type I / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D012008:Recurrence; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D019172:Transplantation Conditioning / Q000379:methods
D000943:Antigens, Differentiation; D018906:Antineoplastic Agents, Alkylating; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007370:Interferon Type I; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7; D003520:Cyclophosphamide