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

Ding, Zhi-Chun; Munn, David H.; Zhou, Gang

doi:10.4161/21624011.2014.954471

Cited by 32 publications

(35 citation statements)

References 12 publications

(13 reference statements)

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“…Chemokine ligand 2 traffics MDSCs that frequently increase in cancer‐bearing hosts . In addition, CCL2 is increased after CP treatment, thereby trafficking MDSCs from the bone marrow . To this end, we examined MDSCs in the spleens of tumor‐bearing and treated mice.…”

Section: Resultsmentioning

confidence: 99%

“…Intriguingly, it has been known that CCL2 increases after CP treatment, thereby leading to trafficking of MDSCs from the bone marrow. (19) Therefore, we hypothesized that the increase in immunosuppressive MDSCs after combination therapy mitigated the reduction in body weight in anti-CTLA-4treated RENCA-bearing mice. However, the depletion of Gr-1 + cells failed to replicate the reduction in body weight observed in anti-CTLA-4-treated RENCA-bearing mice (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…(16)(17)(18) In addition, CCL2 is increased after CP treatment, thereby trafficking MDSCs from the bone marrow. (19) To this end, we examined MDSCs in the spleens of tumor-bearing and treated mice. MDSCs were evaluated according to their expression of Gr-1 and Ly6C among CD11b + cells.…”

Section: Methodsmentioning

confidence: 99%

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Contrasting effects of cyclophosphamide on anti‐CTL‐associated protein 4 blockade therapy in two mouse tumor models

et al. 2017

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Immune checkpoint blockade is a promising anticancer therapy, but must be used in combination with other anticancer therapies to increase its therapeutic efficacy. Cyclophosphamide (CP) is a chemotherapeutic drug that shows immune‐modulating effects. In this study, we examined the effect of CP on anti‐CTL‐associated protein 4 (CTLA‐4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after i.p. injection of CP (100 mg/kg) followed by anti‐CTLA‐4 antibody. However, administration in the reverse order increased apoptosis in tumor‐specific CD8+ T cells. In the RENCA renal carcinoma model, the antitumor effect of combination therapy was marginal and the tumor‐bearing state reduced body weight with an increased serum level of interleukin‐6. Interestingly, although CP monotherapy increased myeloid‐derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti‐CTLA‐4 therapy increased MDSCs only in RENCA‐bearing mice. Additionally, the serum levels of chemokine ligand 2 and C‐X‐C motif chemokine 10 were increased by the combination therapy only in RENCA‐bearing mice and in vivo depletion of Gr‐1+ cells augmented the antitumor effect to some degree. These results reveal a contrasting effect of CP on anti‐CTLA‐4 therapy between the two mouse tumor models. Cyclophosphamide augments the antitumor effect of anti‐CTLA‐4 therapy in CT26‐bearing hosts, whereas CP after anti‐CTLA‐4 therapy attenuates this effect through induction of apoptosis in tumor‐reactive T cells. Alternatively, CP‐induced MDSCs can be increased by anti‐CTLA‐4 therapy only in RENCA‐bearing hosts with an elevated level of interleukin‐6.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Contrasting effects of cyclophosphamide on anti‐CTL‐associated protein 4 blockade therapy in two mouse tumor models

et al. 2017

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“…One described activity of low-dose cyclophosphamide that would possibly impede an optimal immune response is the induction of myeloid-derived suppressor cells (MDSCs) [20,21]. It should be noted, however, that CY-induced changes in the myeloid compartment are complex; for example, they also include induction of dendritic cells, and may depend on CY dose [22,23].…”

Section: Research Papermentioning

confidence: 99%

Low-dose metronomic cyclophosphamide complements the actions of an intratumoral C-class CpG TLR9 agonist to potentiate innate immunity and drive potent T cell-mediated anti-tumor responses

et al. 2019

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The synthetic oligonucleotide SD-101 is a potent and specific agonist for tolllike receptor 9. Intratumoral injection of SD-101 induces significant anti-tumor immunity in preclinical and clinical studies, especially when combined with PD-1 blockade. To build upon this strategy, we studied the enhancement of SD-101 activities by combination with low-dose cyclophosphamide, a well-characterized agent with potentially complementary activities. In multiple mouse tumor models, we demonstrate substantial anti-tumor activity of the combination, compared to each single agent. Combination therapy generated CD8+ T cell dependent immunity leading to rejection of both non-injected and injected tumors and long-term survival, even in very large tumors. Mechanistic studies encompassing global gene expression changes and characterization of immune cell infiltrates show the rapid, sequential induction of innate and adaptive responses and identify discrete contributions of SD-101 and cyclophosphamide. Importantly, these changes were prominent in tumors not injected directly with SD-101. Combination treatment resulted in creation of a permissive environment for a systemic anti-tumor immune response, including a reduction of intratumoral regulatory T cells (Tregs) and an increase in "M1" versus "M2" tumorassociated macrophage (TAM) phenotypes. Additionally, we observed increased immunogenic cell death as well as antigen processing in response to combination treatment.

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“…Chemotherapeutic drugs exert several immune‐enhancing effects, including relief of immune suppressor cells and the induction of immunogenic cancer cell death . Conversely, they induce immunosuppressive conditions, such as immune suppression when administered at higher doses, subsequent recruitment of immune suppressor cells, and the induction of immune checkpoint molecules on cancer cells . Clinically, the combination of ICB Ab therapy with chemotherapy has been reported to show therapeutic efficacy .…”

Section: Introductionmentioning

confidence: 99%

Different sensitivities of senescent breast cancer cells to immune cell‐mediated cytotoxicity

et al. 2019

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Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence‐associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell‐mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA‐MB‐231 and BT‐549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence‐associated β‐galactosidase and promoted the production of pro‐inflammatory cytokines. Importantly, DXR‐treated senescent MDA‐MB‐231 cells showed increased sensitivity to 2 types of immune cell‐mediated cytotoxicity: cytotoxicity of activated CD4+ T cells and Ab‐dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor‐related apoptosis‐inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence‐inducing cyclin‐dependent kinase‐4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell‐mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.

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

Cited by 32 publications

References 12 publications

Contrasting effects of cyclophosphamide on anti‐CTL‐associated protein 4 blockade therapy in two mouse tumor models

Contrasting effects of cyclophosphamide on anti‐CTL‐associated protein 4 blockade therapy in two mouse tumor models

Low-dose metronomic cyclophosphamide complements the actions of an intratumoral C-class CpG TLR9 agonist to potentiate innate immunity and drive potent T cell-mediated anti-tumor responses

Different sensitivities of senescent breast cancer cells to immune cell‐mediated cytotoxicity

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