Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis.
In recent years, immune-based therapies have become an increasingly attractive treatment option for patients with cancer. Cancer immunotherapy is often used in combination with conventional chemotherapy for synergistic effects. The alkylating agent cyclophosphamide (CTX) has been included in various chemoimmunotherapy regimens because of its well-known immunostimulatory effects. Paradoxically, cyclophosphamide can also induce suppressor cells that inhibit immune responses. However, the identity and biologic relevance of these suppressor cells are poorly defined. Here we report that cyclophosphamide treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b(+)Ly6C(hi)CCR2(hi)) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4(+) T cells following cyclophosphamide treatment (CTX+CD4 AT) provoked a robust initial antitumor immune response, but also resulted in enhanced expansion of monocytic myeloid cells. These therapy-induced monocytes inhibited long-term tumor control and allowed subsequent relapse by mediating functional tolerization of antitumor CD4(+) effector cells through the PD-1-PD-L1 axis. PD-1/PD-L1 blockade after CTX+CD4 AT therapy led to persistence of CD4(+) effector cells and durable antitumor effects. Depleting proliferative monocytes by administering low-dose gemcitabine effectively prevented tumor recurrence after CTX+CD4 AT therapy. Similarly, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of cyclophosphamide-based therapy. Besides cyclophosphamide, we found that melphalan and doxorubicin can also induce monocytic myeloid suppressor cells. These findings reveal a counter-regulation mechanism elicited by certain chemotherapeutic agents and highlight the importance of overcoming this barrier to prevent late tumor relapse after chemoimmunotherapy.
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of.
Zhi-Chun
ZC
Ding
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of Department of Gastroenterology, Tongji Hospital, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, Hubei, China.
Xiaoyun
X
Lu
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of.
Miao
M
Yu
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of.
Henrique
H
Lemos
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of.
Lei
L
Huang
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of.
Phillip
P
Chandler
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of.
Kebin
K
Liu
ChemoCentryx Inc., Mountain View, California;
Matthew
M
Walters
ChemoCentryx Inc., Mountain View, California;
Antoni
A
Krasinski
Department of Internal Medicine, University Hospital of Regensburg, Regensburg, Germany; and.
Matthias
M
Mack
Department of Pediatrics and Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota;
Bruce R
BR
Blazar
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of Medicine and.
Andrew L
AL
Mellor
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of Pediatrics, School of Medicine, Georgia Regents University (GRU), Augusta, Georgia;
David H
DH
Munn
Authors' Affiliations: Cancer Immunotherapy, Inflammation and Tolerance Program, Cancer Center; Departments of Medicine and GZHOU@gru.edu.
Gang
G
Zhou
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology*; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
D018906:Antineoplastic Agents, Alkylating; D060890:B7-H1 Antigen; C515335:Ccr2 protein, mouse; C498919:Cd274 protein, mouse; D007166:Immunosuppressive Agents; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D054390:Receptors, CCR2; D003841:Deoxycytidine; D004317:Doxorubicin; D003520:Cyclophosphamide; D008558:Melphalan; D000093542:Gemcitabine