Immunosuppressive Myeloid Cells Induced by Chemotherapy Attenuate Antitumor CD4+ T-Cell Responses through the PD-1–PD-L1 Axis

Abstract

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 due to its well-known immunostimulatory effects. Paradoxically, CTX can also induce suppressor cells that inhibit immune responses. However, the identity and biological relevance of these suppressor cells are poorly defined. Here we report that CTX treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b+Ly6ChiCCR2hi) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4+ T cells following CTX 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. Likewise, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of CTX-based therapy. Besides CTX, 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.

Chemotherapy-induced myeloid suppressor cells and antitumor immunity: The Janus face of chemotherapy in immunomodulation

“…We subsequently showed that selective depletion of CTX-MDSCs following chemoimmunotherapy in a mouse model of Bcell lymphoma significantly improved long-term survival, providing evidence that CTX-MDSCs contribute to tumor immune evasion and relapse. 5 Our study provides new insights regarding the ontogeny of CTX-MDSCs. We found that the doses of CTX that result in significant myeloid cell expansion in mice fell into the medium-high range (100-300 mg/kg), whereas metronomic CTX doses (10-40 mg/kg) failed to induce myeloid cells.…”

“…At the molecular level, granulocyte macrophage colony stimulating factor (GM-CSF), colony stimulating factor 3 (G-CSF/Csf3), IL-1b, IL-6, and (C-C) motif chemokine ligand 2 (CCL2) are among inflammatory mediators induced after CTX treatment, 6,7 candidate effector molecules that may promote the expansion of CTXMDSCs. We showed that this inflammatory milieu was further heightened by the Besides CTX, we found that 2 other widely used anticancer drugs (doxorubicin and melphalan) exhibit a similar effect, 5 suggesting that induction of myeloid suppressor cells is an inherent property of certain anticancer drugs. Future studies should identify additional MDSC-inducing chemotherapeutic agents.…”

“…3,4 We recently reported that CTX can induce the expansion of myeloid cells consisting of monocytic and granulocytic subsets, and only the monocytic subset harbors T-cell suppressive activity. 5 We herein term these CTX-induced immunosuppressive monocytic myeloid cells "CTX-MDSCs". We subsequently showed that selective depletion of CTX-MDSCs following chemoimmunotherapy in a mouse model of Bcell lymphoma significantly improved long-term survival, providing evidence that CTX-MDSCs contribute to tumor immune evasion and relapse.…”

Functio Laesa: Cancer Inflammation and Therapeutic Resistance

“…[42][43][44][45] These findings form the basis for early-phase clinical trials evaluating immune checkpoint inhibitors in combination with strategies designed to inhibit the recruitment of myeloid cells (eg, inhibitors of FAK, CCR2, and CXCR2) or deplete myeloid cells (eg, CSF1R antagonists; Table 2). Combining multiple immune modulatory agents, though, poses challenges in determining the contribution of each therapeutic intervention to observed clinical responses.…”

Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity

“…50 Several studies also support the relevance of Tim3 blockade for treatment of various cancer types and remarkable synergistic effects have been observed in combined therapies that target Tim3 and PD-1 (for a review see ref)…”