Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity

Silva, Rosa Barreira da; Leitao, Ricardo; Pechuan-Jorge, Ximo; Werneke, Scott; Oeh, Jason; Javinal, Vincent; Wang, Yingyun; Phung, Wilson; Everett, Christine; Nonomiya, Jim; Arnott, David; Lu, Cheng; Hsiao, Yi-Chun; Koerber, James T.; Hötzel, Isidro; Ziai, James; Modrušan, Zora; Pillow, Thomas H.; Roose‐Girma, Merone; Schartner, Jill; Merchant, Mark; Rutz, Sascha; Eidenschenk, Céline; Mellman, Ira; Albert, Matthew L.

doi:10.1038/s41590-022-01153-x

Cited by 22 publications

(24 citation statements)

References 57 publications

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“…A recent study targeted TAMs by modulating glutaminyl-peptide cyclotransferase-like (QPCTL), an intracellular enzyme that modifies chemokine CCL2 and CCL7 to protect them from the proteolytic degradation [104]. In mice bearing either EO771 BRCA tumors or LL/2 lung carcinomas, ablating QPCTL function resulted in the production of nonfunctional forms of chemokines, thus shifting the CCL2-CCR2 axis and restricting monocyte trafficking.…”

Section: Box 2 Emerging Tam-targeted Therapeutic Candidatesmentioning

confidence: 99%

Macrophage diversity in cancer revisited in the era of single-cell omics

Black

Qian

2022

Trends in Immunology

243

225

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Section: Box 2 Emerging Tam-targeted Therapeutic Candidatesmentioning

confidence: 99%

Macrophage diversity in cancer revisited in the era of single-cell omics

Black

Qian

2022

Trends in Immunology

243

225

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“…Currently, there are three classes of CD47-SIRPα signaling pathway inhibitors: blocking CD47 molecules, blocking SIRPα molecules, or small molecules that inhibit QPCT/L ( Barreira da Silva et al, 2022 ; Logtenberg et al, 2020 ). To determine whether QPCT/L activity in senescent cells was required for SCES, we treated primary IPF-derived lung fibroblasts with the QPCTL inhibitor SEN177 ( Jimenez-Sanchez et al, 2015 ) followed by senescence induction with palbociclib.…”

Section: Resultsmentioning

confidence: 99%

Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis

Schloesser

Lindenthal

Sauer

et al. 2022

Journal of Cell Biology

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Progressive accrual of senescent cells in aging and chronic diseases is associated with detrimental effects in tissue homeostasis. We found that senescent fibroblasts and epithelia were not only refractory to macrophage-mediated engulfment and removal, but they also paralyzed the ability of macrophages to remove bystander apoptotic corpses. Senescent cell-mediated efferocytosis suppression (SCES) was independent of the senescence-associated secretory phenotype (SASP) but instead required direct contact between macrophages and senescent cells. SCES involved augmented senescent cell expression of CD47 coinciding with increased CD47-modifying enzymes QPCT/L. SCES was reversible by interfering with the SIRPα-CD47-SHP-1 axis or QPCT/L activity. While CD47 expression increased in human and mouse senescent cells in vitro and in vivo, another ITIM-containing protein, CD24, contributed to SCES specifically in human epithelial senescent cells where it compensated for genetic deficiency in CD47. Thus, CD47 and CD24 link the pathogenic effects of senescent cells to homeostatic macrophage functions, such as efferocytosis, which we hypothesize must occur efficiently to maintain tissue homeostasis.

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“…Diving deeper, we investigated whether these tumor immune infiltrates were pro- or anti-tumor. Markers of immunosuppression, alternative macrophage activation, pro-angiogenic, hypoxia-related and inhibitory molecules gene signature(31) including Ccl5/RANTES, Ccl8/MCP-2, Cxcl1/CXCL1, Cxcl2/CXCL2, Mmp9/MMP9, Vegfa/VEGF, Tgfb1/TGF-β1, Tnf/TNF-α, Fn1/FN (Fibronectin), Spp1/OPN (Osteopontin), Hilpda/HIG, Hmox1/HO-1, Pdcd1/PD-1, Cd274/PD-L1, Lag3/LAG-3 and Havcr2/TIM-3, were expressed by these immune cells. Comparative analysis between docetaxel treatment vs. vehicle control of the pro-tumor gene signature in immune cells demonstrated an upregulation of this immunosuppressive gene signature upon docetaxel treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Diving deeper, we investigated whether these tumor immune infiltrates were pro-or anti-tumor. Markers of immunosuppression, alternative macrophage activation, pro-angiogenic, hypoxia-related and inhibitory molecules gene signature (31) Having found that IL-6 and G-CSF levels were increased in plasma after DTX treatment (Fig. 5A), we asked whether the molecular signaling mechanisms were similar in vivo and in vitro (Fig.…”

Section: Chemotherapy Induced Systemic Response and Altered Tumor Imm...mentioning

confidence: 99%

“…Diving deeper, we investigated whether these tumor immune infiltrates were pro-or anti-tumor. Markers of immunosuppression, alternative macrophage activation, pro-angiogenic, hypoxia-related and inhibitory molecules gene signature (31) S5A). The analysis depicted the relative abundance of cancer cells and non-immune stromal cells was significantly altered with increased cancer cells and decreased fibroblasts/CAFs, cancer associated fibroblasts (CAFs), fibrocytes, adipocytes/mammary epithelial cells (Adipo/MEpCs) upon docetaxel treatment compared to vehicle treated control mammary tumor (Fig.…”

Section: Chemotherapy Induced Systemic Response and Altered Tumor Imm...mentioning

confidence: 99%

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Taxane chemotherapy leads to breast cancer dormancy escape by stromal injury mediated IL-6/MAP2K signaling

Ganesan

Bhasin

Krishnan

et al. 2022

Preprint

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A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and G-CSF, that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance, as well as an altered tumor microenvironment with augmented pro-tumor immune signaling. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.

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Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity

Cited by 22 publications

References 57 publications

Macrophage diversity in cancer revisited in the era of single-cell omics

Macrophage diversity in cancer revisited in the era of single-cell omics

Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis

Taxane chemotherapy leads to breast cancer dormancy escape by stromal injury mediated IL-6/MAP2K signaling

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