Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner

Holmgaard, Rikke; Zamarin, Dmitriy; Li, Yanyun; Gasmi, Billel; Munn, David H.; Allison, James P.; Merghoub, Taha; Wolchok, Jedd D.

doi:10.1016/j.celrep.2015.08.077

Cited by 372 publications

(326 citation statements)

References 21 publications

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“…It has been previously shown that tryptophan depletion by cancer cell-expressed IDO1 could lead to the T cell anergy and activation of immunosuppressive Tregs and MDSCs. 46,47 Currently, drugs targeting IDO1 pathway are in clinical trials to reverse the tumor-induced immunosuppression. 47 In accordance with our data, a recent report demonstrated that restoration of p53 activity via nutlin-3a was able to induce ICD and promote CD8 T cell-dependent anti-tumor immunity in mice bearing EL4 tumor.…”

Section: Discussionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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Section: Discussionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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“…The role of CSF-1 may be tumor modeldependent as distinct myeloid subsets dominate in different tumor models. Some tumor models are more infiltrated with and more dependent on MDSCs, 22,40,51 whereas others have few MDSCs and are primarily dominated by macrophages. 23,34 Recruitment and differentiation of myeloid cells in tumors are complex processes regulated by multiple pathways, which may lead to differential responses to CSF-1R inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously described that overexpression of IDO by B16 tumor cells (B16-IDO) promotes tumor recruitment of large numbers of highly suppressive MDSCs. 51 To this end, B16-IDO tumor-bearing mice were treated with aCSF-1R in combination with aPD-1 C aCTLA-4 antibodies. aCSF-1R alone had no effect on the progression of B16-IDO tumors (Fig.…”

Section: The Combinatorial Antitumor Effect Of Csf-1r and T Cell Checmentioning

confidence: 99%

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

et al. 2016

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Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy.Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection.

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“…High expression of IDO results in an immunosuppressive tumor microenvironment with impaired activity of effector T cells, increased differentiation of regulatory T (T reg ) cells and decreased dendritic cell (DC) functions. 26 Treatment with IDO inhibitor reversed suppression by decreasing numbers of myeloid-derived suppressor cells (MDSCs) and T reg s. 27 Expression of IDO is a critical resistance mechanism to CTLA-4 blockade and dual inhibition with CTLA-4 and PD-1 or PD-L1 blockade leads to synergistic antitumor effects in melanoma models. 28,29 Therefore, preclinical data provides a strong theoretical basis for exploration of clinical combinations of IDO inhibitors and immune checkpoint inhibitors.…”

Section: Combination Strategiesmentioning

confidence: 99%