Human lung adenocarcinoma CD47 is upregulated by interferon-γ and promotes tumor metastasis

Qu, Shuang; Jiao, Zhen; Lu, Geng; Xu, Jiahan; Yao, Bing; Wang, Ting; Wang, Jun; Yao, Yongzhong; Yan, Xin; Wang, Tao; Liang, Hongwei; Zen, Ke

doi:10.1016/j.omto.2022.04.011

Cited by 7 publications

(10 citation statements)

References 48 publications

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“…CD47 overexpression is thought to be associated with advanced cancers 16 – 18 . Contrastingly, we observed that metastatic prostate tumors frequently expressed lower CD47 levels, compared with primary tumors and benign hyperplasia samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination

Chou,

Hung,

Chiu

et al. 2023

Nat Commun

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While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel this engulfment. Here we report that the reverse signaling using CD47 as a receptor additionally enhances a pro-survival function of prostate cancer cells under phagocytic attack. Although low CD47-expressing cancer cells still allow phagocytosis, the reverse signaling delays the process, leading to incomplete digestion of the entrapped cells and subsequent tumor hybrid cell (THC) formation. Viable THCs acquire c-Myc from parental cancer cells to upregulate both M1- and M2-like macrophage polarization genes. Consequently, THCs imitating dual macrophage features can confound immunosurveillance, gaining survival advantage in the host. Furthermore, these cells intrinsically express low levels of androgen receptor and its targets, resembling an adenocarcinoma-immune subtype of metastatic castration-resistant prostate cancer. Therefore, phagocytosis-generated THCs may represent a potential target for treating the disease.

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Section: Resultsmentioning

confidence: 99%

Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination

Chou,

Hung,

Chiu

et al. 2023

Nat Commun

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“…In our experimental model, tumors were not established, avoiding the circulating monocyte reprogramming. Therefore, we can assume that they had antitumor activity and responded against cancer cells; however, more studies are needed to confirm this, including CD47 expression in cancer cells, as a surface protein that interacts with monocytes [ 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine Differentiation of Lung Cancer Cells Impairs the Activation of Antitumor Cytotoxic Responses in Mice

Fosado

Soto-Hernández

Núñez-Anita

et al. 2023

IJMS

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Lung cancer has the highest mortality among all types of cancer; during its development, cells can acquire neural and endocrine properties that affect tumor progression by releasing several factors, some acting as immunomodulators. Neuroendocrine phenotype correlates with invasiveness, metastasis, and low survival rates. This work evaluated the effect of neuroendocrine differentiation of adenocarcinoma on the mouse immune system. A549 cells were treated with FSK (forskolin) and IBMX (3-Isobutyl-1-methylxanthine) for 96 h to induce neuroendocrine differentiation (NED). Systemic effects were assessed by determining changes in circulating cytokines and immune cells of BALB/c mice immunized with PBS, undifferentiated A549 cells, or neuroendocrine A549NED cells. A549 cells increased circulating monocytes, while CD4+CD8− and CD4+CD8+ T cells increased in mice immunized with neuroendocrine cells. IL-2 and IL-10 increased in mice that received untreated A549 cells, suggesting that the immune system mounts a regulated response against adenocarcinoma, which did not occur with A549NED cells. Cocultures demonstrated the cytotoxic capacity of PBMCs when confronted with A549 cells, while in the presence of neuroendocrine cells they not only were unable to show cytolytic activity, but also lost viability. Neuroendocrine differentiation seems to mount less of an immune response when injected in mice, which may contribute to the poor prognosis of cancer patients affected by this pathology.

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“…Ye and colleagues first described induction of CD47 by IFNγ in lung cancer cells through a JAK-STAT1-IRF1 signaling pathway [226]. Later, this mechanism was confirmed by Qu et al who demonstrated that IRF1 binds to the CD47 promoter and induces its transcription [130,226].…”

Section: Pathways To Cd47 Upregulation In Nsclcmentioning

confidence: 91%

“…Given that CD47 is expressed in up to 84% of NSCLC, oncogenes are unlikely to account for CD47 upregulation in all cases. Studies conducted in various models have established that IFNγ regulates CD47 expression in NSCLC [130,226]. IFNγ is a proinflammatory cytokine that can directly induce apoptosis in tumor cells and stimulate innate and adaptive immune activation.…”

Section: Pathways To Cd47 Upregulation In Nsclcmentioning

confidence: 99%

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CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer

Lau,

Khavkine Binstock,

Thu

2023

Cancers

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The success of PD-1/PD-L1-targeted therapy in lung cancer has resulted in great enthusiasm for additional immunotherapies in development to elicit similar survival benefits, particularly in patients who do not respond to or are ineligible for PD-1 blockade. CD47 is an immunosuppressive molecule that binds SIRPα on antigen-presenting cells to regulate an innate immune checkpoint that blocks phagocytosis and subsequent activation of adaptive tumor immunity. In lung cancer, CD47 expression is associated with poor survival and tumors with EGFR mutations, which do not typically respond to PD-1 blockade. Given its prognostic relevance, its role in facilitating immune escape, and the number of agents currently in clinical development, CD47 blockade represents a promising next-generation immunotherapy for lung cancer. In this review, we briefly summarize how tumors disrupt the cancer immunity cycle to facilitate immune evasion and their exploitation of immune checkpoints like the CD47–SIRPα axis. We also discuss approved immune checkpoint inhibitors and strategies for targeting CD47 that are currently being investigated. Finally, we review the literature supporting CD47 as a promising immunotherapeutic target in lung cancer and offer our perspective on key obstacles that must be overcome to establish CD47 blockade as the next standard of care for lung cancer therapy.

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Human lung adenocarcinoma CD47 is upregulated by interferon-γ and promotes tumor metastasis

Cited by 7 publications

References 48 publications

Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination

Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination

Neuroendocrine Differentiation of Lung Cancer Cells Impairs the Activation of Antitumor Cytotoxic Responses in Mice

CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer

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