In a study reported in Cancer Research, Ding and colleagues identified mechanisms by which cyclophosphamide induces suppressor cells that inhibit immune response and predispose to loss of tumor control. They found that cyclophosphamide treatment induces expansion of inflammatory monocytic myeloid cells (CD11b+Ly6ChiCCR2hi) that exert immunosuppressive activities.
Adoptive transfer of tumor-specific CD4-positive T cells after cyclophosphamide treatment in mice with advanced lymphoma resulted in initial antitumor immune response, but also increased expansion of the inflammatory monocytic myeloid cells. This expansion resulted in loss of long-term tumor control and permitted recurrence by supporting functional tolerance of the antitumor CD4-positive effector cells via the PD-1–PD-L1 axis. Blockade of PD-1/PD-L1 after treatment with cyclophosphamide and adoptive transfer of the tumor-specific CD4-positive T cells resulted in persistence of the CD4-positive effector cells and durable antitumor effects.
In addition, use of low-dose gemcitabine to reduce levels of the proliferative monocytes prevented tumor recurrence after treatment with cyclophosphamide and adoptive transfer. Further, inhibition of the monocytes via disruption of the CCR2 signaling pathway augmented the efficacy of cyclophosphamide. The investigators found that melphalan and doxorubicin can also induce expansion of monocytic myeloid suppressor cells.
The investigators concluded, “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.” ■
Ding ZC, et al: Cancer Res 74:3441-3453, 2014.