Bibliographic Details
| 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 |
