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Anaplastic Lymphoma Kinase (ALK) Inhibitors Enhance Phagocytosis Induced by CD47 Blockade in Sensitive and Resistant ALK-Driven Malignancies

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Title: Anaplastic Lymphoma Kinase (ALK) Inhibitors Enhance Phagocytosis Induced by CD47 Blockade in Sensitive and Resistant ALK-Driven Malignancies
Authors: Federica Malighetti, Matteo Villa, Mario Mauri, Simone Piane, Valentina Crippa, Ilaria Crespiatico, Federica Cocito, Elisa Bossi, Carolina Steidl, Ivan Civettini, Chiara Scollo, Daniele Ramazzotti, Carlo Gambacorti-Passerini, Rocco Piazza, Luca Mologni, Andrea Aroldi
Source: Biomedicines, Vol 12, Iss 12, p 2819 (2024)
Publisher Information: MDPI AG, 2024.
Publication Year: 2024
Collection: LCC:Biology (General)
Subject Terms: ALK, macrophages, tumor immunology, CD47, TKIs (tyrosine kinase inhibitors), neuroblastoma, Biology (General), QH301-705.5
More Details: Background: Anaplastic lymphoma kinase (ALK) plays a role in the development of lymphoma, lung cancer and neuroblastoma. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, relapse remains a challenge due to on-target mutations and off-target resistance mechanisms. ALK-positive (ALK+) tumors can evade the immune system, partly through tumor-associated macrophages (TAMs) that facilitate immune escape. Cancer cells use “don’t eat me” signals (DEMs), such as CD47, to resist TAMs-mediated phagocytosis. TKIs may upregulate pro-phagocytic stimuli (i.e., calreticulin, CALR), suggesting a potential therapeutic benefit in combining TKIs with an anti-CD47 monoclonal antibody (mAb). However, the impact of this combination on both TKIs-sensitive and resistant ALK+ tumors requires further investigation. Methods: A panel of TKIs-sensitive and resistant ALK+ cancer subtypes was assessed for CALR and CD47 expression over time using flow cytometry. Flow cytometry co-culture and fluorescent microscopy assays were employed to evaluate phagocytosis under various treatment conditions. Results: ALK inhibitors increased CALR expression in both TKIs-sensitive and off-target resistant ALK+ cancer cells. Prolonged TKIs exposure also led to CD47 upregulation. The combination of ALK inhibitors and anti-CD47 mAb significantly enhanced phagocytosis compared to anti-CD47 alone, as confirmed by flow cytometry and fluorescent microscopy. Conclusions: Anti-CD47 mAb can quench DEMs while exposing pro-phagocytic signals, promoting tumor cell phagocytosis. ALK inhibitors induced immunogenic cell damage by upregulating CALR in both sensitive and off-target resistant tumors. Continuous TKIs exposure in off-target resistant settings also resulted in the upregulation of CD47 over time. Combining TKIs with a CD47 blockade may offer therapeutic benefits in ALK+ cancers, especially in overcoming off-target resistance where TKIs alone are less effective.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2227-9059
Relation: https://www.mdpi.com/2227-9059/12/12/2819; https://doaj.org/toc/2227-9059
DOI: 10.3390/biomedicines12122819
Access URL: https://doaj.org/article/067420bbdfad46bba2b3a23caffce82d
Accession Number: edsdoj.067420bbdfad46bba2b3a23caffce82d
Database: Directory of Open Access Journals
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  Data: Anaplastic Lymphoma Kinase (ALK) Inhibitors Enhance Phagocytosis Induced by CD47 Blockade in Sensitive and Resistant ALK-Driven Malignancies
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  Data: <searchLink fieldCode="AR" term="%22Federica+Malighetti%22">Federica Malighetti</searchLink><br /><searchLink fieldCode="AR" term="%22Matteo+Villa%22">Matteo Villa</searchLink><br /><searchLink fieldCode="AR" term="%22Mario+Mauri%22">Mario Mauri</searchLink><br /><searchLink fieldCode="AR" term="%22Simone+Piane%22">Simone Piane</searchLink><br /><searchLink fieldCode="AR" term="%22Valentina+Crippa%22">Valentina Crippa</searchLink><br /><searchLink fieldCode="AR" term="%22Ilaria+Crespiatico%22">Ilaria Crespiatico</searchLink><br /><searchLink fieldCode="AR" term="%22Federica+Cocito%22">Federica Cocito</searchLink><br /><searchLink fieldCode="AR" term="%22Elisa+Bossi%22">Elisa Bossi</searchLink><br /><searchLink fieldCode="AR" term="%22Carolina+Steidl%22">Carolina Steidl</searchLink><br /><searchLink fieldCode="AR" term="%22Ivan+Civettini%22">Ivan Civettini</searchLink><br /><searchLink fieldCode="AR" term="%22Chiara+Scollo%22">Chiara Scollo</searchLink><br /><searchLink fieldCode="AR" term="%22Daniele+Ramazzotti%22">Daniele Ramazzotti</searchLink><br /><searchLink fieldCode="AR" term="%22Carlo+Gambacorti-Passerini%22">Carlo Gambacorti-Passerini</searchLink><br /><searchLink fieldCode="AR" term="%22Rocco+Piazza%22">Rocco Piazza</searchLink><br /><searchLink fieldCode="AR" term="%22Luca+Mologni%22">Luca Mologni</searchLink><br /><searchLink fieldCode="AR" term="%22Andrea+Aroldi%22">Andrea Aroldi</searchLink>
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  Data: Biomedicines, Vol 12, Iss 12, p 2819 (2024)
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  Data: MDPI AG, 2024.
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  Data: 2024
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  Data: LCC:Biology (General)
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  Data: <searchLink fieldCode="DE" term="%22ALK%22">ALK</searchLink><br /><searchLink fieldCode="DE" term="%22macrophages%22">macrophages</searchLink><br /><searchLink fieldCode="DE" term="%22tumor+immunology%22">tumor immunology</searchLink><br /><searchLink fieldCode="DE" term="%22CD47%22">CD47</searchLink><br /><searchLink fieldCode="DE" term="%22TKIs+%28tyrosine+kinase+inhibitors%29%22">TKIs (tyrosine kinase inhibitors)</searchLink><br /><searchLink fieldCode="DE" term="%22neuroblastoma%22">neuroblastoma</searchLink><br /><searchLink fieldCode="DE" term="%22Biology+%28General%29%22">Biology (General)</searchLink><br /><searchLink fieldCode="DE" term="%22QH301-705%2E5%22">QH301-705.5</searchLink>
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  Label: Description
  Group: Ab
  Data: Background: Anaplastic lymphoma kinase (ALK) plays a role in the development of lymphoma, lung cancer and neuroblastoma. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, relapse remains a challenge due to on-target mutations and off-target resistance mechanisms. ALK-positive (ALK+) tumors can evade the immune system, partly through tumor-associated macrophages (TAMs) that facilitate immune escape. Cancer cells use “don’t eat me” signals (DEMs), such as CD47, to resist TAMs-mediated phagocytosis. TKIs may upregulate pro-phagocytic stimuli (i.e., calreticulin, CALR), suggesting a potential therapeutic benefit in combining TKIs with an anti-CD47 monoclonal antibody (mAb). However, the impact of this combination on both TKIs-sensitive and resistant ALK+ tumors requires further investigation. Methods: A panel of TKIs-sensitive and resistant ALK+ cancer subtypes was assessed for CALR and CD47 expression over time using flow cytometry. Flow cytometry co-culture and fluorescent microscopy assays were employed to evaluate phagocytosis under various treatment conditions. Results: ALK inhibitors increased CALR expression in both TKIs-sensitive and off-target resistant ALK+ cancer cells. Prolonged TKIs exposure also led to CD47 upregulation. The combination of ALK inhibitors and anti-CD47 mAb significantly enhanced phagocytosis compared to anti-CD47 alone, as confirmed by flow cytometry and fluorescent microscopy. Conclusions: Anti-CD47 mAb can quench DEMs while exposing pro-phagocytic signals, promoting tumor cell phagocytosis. ALK inhibitors induced immunogenic cell damage by upregulating CALR in both sensitive and off-target resistant tumors. Continuous TKIs exposure in off-target resistant settings also resulted in the upregulation of CD47 over time. Combining TKIs with a CD47 blockade may offer therapeutic benefits in ALK+ cancers, especially in overcoming off-target resistance where TKIs alone are less effective.
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  Data: https://www.mdpi.com/2227-9059/12/12/2819; https://doaj.org/toc/2227-9059
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  Data: 10.3390/biomedicines12122819
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