Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity

Perry, Curtis J.; Muñoz-Rojas, Andrés R; Meeth, Katrina; Kellman, Laura N; Amezquita, Robert A.; Thakral, Durga; Du, Victor Y.; Wang, Jake Xiao; Damsky, William; Kuhlmann, Alexandra; Sher, Joel W; Bosenberg, Marcus W.; Miller‐Jensen, Kathryn; Kaech, Susan M.

doi:10.1084/jem.20171435

Cited by 117 publications

(109 citation statements)

References 45 publications

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“…Such single-cell measurements are important because macrophage populations display significant cell-to-cell heterogeneity in their responses even following acute stimulation with LPS 16–18 . The heterogeneity observed in vitro is also reflected in vivo in numerous studies of macrophage heterogeneity in a variety of disease states, including cancer, liver cirrhosis, and wound healing 19–23 . It is therefore important to characterize how individual macrophages respond to and resolve conflicting cues to coordinate a cohesive immune response within complex tissue microenvironments.…”

Section: Introductionmentioning

confidence: 98%

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Muñoz-Rojas

Kelsey

Pappalardo

et al. 2020

Preprint

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14Macrophages are innate immune cells that contribute to fighting infections, tissue repair, and 15 maintaining tissue homeostasis. To enable such functional diversity, macrophages resolve 16 potentially conflicting cues in the microenvironment via mechanisms that remain unclear. Here, 17we used single-cell RNA sequencing to explore how individual macrophages respond when co-18 stimulated with the inflammatory stimuli, LPS+IFN-γ, and the resolving cytokine, IL-4. We found 19 that co-stimulated macrophages displayed a distinct global transcriptional program. However, 20 variable negative cross-regulation between some LPS+IFN-γ-and IL-4-specific genes resulted in 21 significant cell-to-cell heterogeneity in transcription. Interestingly, negative cross-regulation led 22to mutually exclusive expression of the T-cell-polarizing cytokines Il6 and Il12b versus the IL-4-23 associated factors Arg1 and Chil3 in single co-stimulated macrophages, and single-cell secretion 24 measurements showed that these specialized functions were maintained for at least 48 hours. 25Overall, our study suggests that increasing functional diversity in the population is one strategy 26 macrophages use to respond to conflicting environmental cues. 27 LPS+IFN-γ or the IL-4 transcriptional program in response to co-stimulation. 131 132 Co-stimulation with LPS+IFN-γ and IL-4 induces transcriptional cross-regulation that 133 varies substantially across individual cells 134We next focused on how co-stimulation with LPS+IFN-γ and IL-4 affected the expression 135 of genes uniquely upregulated by either LPS+IFN-γ or IL-4 alone ( Fig. 2a), which we refer to as 136 the core gene programs. For both LPS+IFN-γ-and IL-4-induced genes, co-stimulation with the 137 other cue caused both transcriptional upregulation and inhibition in a subset of core genes 138 belonging to each program, consistent with our own and previously reported observations 14 . 139Among the LPS+IFN-γ-induced core genes, 87 were inhibited by co-stimulation and 97 were 140 augmented by co-stimulation, while among the IL-4-induced core genes, 196 were inhibited and 141 16 were augmented by co-stimulation (Fig. 2b). 142We compared observations from our single-cell dataset to population-level RT-qPCR data 514

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Section: Introductionmentioning

confidence: 98%

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Muñoz-Rojas

Kelsey

Pappalardo

et al. 2020

Preprint

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“…Recently, multiple studies have demonstrated that pro-inflammatory TAMs inhibit tumor growth (Hoves et al, 2018;Perry et al, 2018). Our RNA sequencing data of TAMs from JHU083 treated mice demonstrated an increase in the pro-inflammatory cytokine, Tnf.…”

Section: Targeting Glutamine Metabolism Promotes the Reprogramming Ofmentioning

confidence: 71%

Targeting glutamine metabolism enhances tumor specific immunity by inhibiting the generation of MDSCs and reprogramming tumor associated macrophages

Sun

Zhao

et al. 2019

Preprint

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“…reported, TAM in melanoma express PD‐1, and the blockade of PD‐ligand 1/PD‐1 signaling induces M1‐like responses, leading to an antitumor immune response in melanomas. In addition, Perry et al . reported that reprogramming TAM into inflammatory phenotypes by targeting CD40 and CD115 suppresses melanoma growth in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…6 Moreover, as Gordon et al 7 reported, TAM in melanoma express PD-1, and the blockade of PD-ligand 1/PD-1 signaling induces M1-like responses, leading to an antitumor immune response in melanomas. In addition, Perry et al 8 reported that reprogramming TAM into inflammatory phenotypes by targeting CD40 and CD115 suppresses melanoma growth in vivo. In aggregate, TAM were reported as an optimal target for immunotherapy, 6 and TAMrelated products could even be biomarkers for the efficacy and immune related adverse events in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Two cases of dabrafenib and trametinib therapy‐failed advanced melanoma successfully controlled by nivolumab monotherapy

Sato

Fujimura

Kambayashi

et al. 2018

The Journal of Dermatology

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Although therapies for advanced melanoma have been greatly improved by the development of immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors, there are still many concerns about the administration of these novel drugs. Therefore, to combine these therapies sequentially at appropriate time points of the disease is important. In this report, we report two cases in which dabrafenib and trametinib therapy for advanced melanoma failed but were successfully controlled by nivolumab monotherapy, and investigated the sera sCD163, CCL22 and CXCL10 as biomarkers for tumor progression. Interestingly, the sera levels of sCD163, CXCL10 and CCL22, both of which are produced by activated tumor-associated macrophages, were increased in parallel with the tumor progression in each case. Because this report presents only two cases, further data will need to be accumulated to provide more fundamental insights into the usefulness of these biomarkers for predicting disease progression in melanoma.

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Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity

Abstract: Perry et al. show that myeloid-targeted immunotherapy with a combination of anti-CD40 and CSF-1R inhibition synergistically induces a proinflammatory microenvironment that suppresses CPI-resistant tumors in a TNF-α– and IFN-γ–dependent manner.

Cited by 117 publications

References 45 publications

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells

Targeting glutamine metabolism enhances tumor specific immunity by inhibiting the generation of MDSCs and reprogramming tumor associated macrophages

Two cases of dabrafenib and trametinib therapy‐failed advanced melanoma successfully controlled by nivolumab monotherapy

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