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Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+
T-cell responses through the PD-1-PD-L1 axis
#MMPMID24780756
Ding ZC
; Lu X
; Yu M
; Lemos H
; Huang L
; Chandler P
; Liu K
; Walters M
; Krasinski A
; Mack M
; Blazar BR
; Mellor AL
; Munn DH
; Zhou G
Cancer Res
2014[Jul]; 74
(13
): 3441-53
PMID24780756
show ga
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.
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