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New hope for tumor immunotherapy: the macrophage-related "do not eat me" signaling pathway.

ABSTRACT: The "do not eat me" signaling pathway is extremely active in tumor cells, providing a means for these cells to elude macrophage phagocytosis and escape immune surveillance. Representative markers of this pathway, such as CD47 and CD24, are highly expressed in numerous tumors. The interaction of SIRPα with CD47 reduces the accumulation of non-myosin ⅡA on the cell membrane. The combination of CD24 and Siglec10 ultimately leads to the recruitment of SHP-1 or SHP-2 to reduce signal transduction. Both of them weaken the ability of macrophages to engulf tumor cells. Blocking the mutual recognition between CD47-SIRPα or CD24-Siglec10 using large molecular proteins or small molecular drugs represents a promising avenue for tumor immunotherapy. Doing so can inhibit signal transduction and enhance macrophage clearance rates of cancer cells. In this paper, we summarize the characteristics of the drugs that affect the "do not eat me" signaling pathway via classical large molecular proteins and small molecule drugs, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways. We expect it will offer insight into the development of new drugs centered on blocking the "do not eat me" signaling pathway.

SUBMITTER: Deng H

PROVIDER: S-EPMC10358856 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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New hope for tumor immunotherapy: the macrophage-related "do not eat me" signaling pathway.

Deng Han H Wang Guan G Zhao Shengyan S Tao Yiran Y Zhang Zhixiong Z Yang Jinliang J Lei Yi Y

Frontiers in pharmacology 20230706

The "do not eat me" signaling pathway is extremely active in tumor cells, providing a means for these cells to elude macrophage phagocytosis and escape immune surveillance. Representative markers of this pathway, such as CD47 and CD24, are highly expressed in numerous tumors. The interaction of SIRPα with CD47 reduces the accumulation of non-myosin ⅡA on the cell membrane. The combination of CD24 and Siglec10 ultimately leads to the recruitment of SHP-1 or SHP-2 to reduce signal transduction. Bo ...[more]

PMID: 37484024

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Project description:Tumor‑associated macrophage (TAMs) are paramount for tumor progression and immune tolerance in the tumor microenvironment of various types of cancer, including liver cancer. The aim of the present study was to investigate the effect of vascular endothelial growth factor (VEGF) inhibition on TAM polarization and function during their interactions with macrophages and liver cancer cells. TAMs were induced by culturing M0 macrophages with cancer cell‑conditioned medium. TAMs cultured with cancer cell‑conditioned medium and vascular endothelial growth factor (VEGF) inhibitor were defined as modified TAMs, and the expression levels of TAM‑associated markers and VEGF receptor 2 were evaluated using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The effects of TAMs and modified TAMs on cancer cell proliferation and migration were investigated using conditioned medium. Programmed death‑ligand 1 (PD‑L1) mRNA expression in modified TAMs and cancer cells cultured in modified TAM‑conditioned medium (TAM‑CM) for 48 h was examined using RT‑qPCR. In order to investigate signaling pathways in macrophages, western blot analysis was performed. CD163 and CD206 and M2 macrophage marker expression was upregulated in TAMs and modified TAMs. Modified TAM‑CM exhibited a decreased ability to promote cancer cell proliferation and migration in comparison with the use of TAM‑CM. The VEGF concentration was significantly higher in the TAMs than in M0 macrophages; however, the modified TAMs displayed a significantly lower VEGF secretion than TAMs. PD‑L1 expression was decreased in modified TAMs as compared with TAMs. Western blot analysis revealed that the Akt/mTOR signaling pathway was significantly suppressed in the modified TAMs compared with TAMs. It was observed that TAMs cultured in a VEGF‑depleted environment displayed lower secretion levels of cytokines involved in tumor progression and a decreased immune tolerance‑inducing ability. On the whole, the results of the present study suggested that VEGF inhibition in TAMs may be a potential therapeutic target for liver cancer.

Project description:Cancer stands as one of the prominent global causes of death, with its incidence burden continuously increasing, leading to a substantial rise in mortality rates. Cancer treatment has seen the development of various strategies, each carrying its drawbacks that can negatively impact the quality of life for cancer patients. The challenge remains significant within the medical field to establish a definitive cancer treatment that minimizes complications and limitations. In the forthcoming years, exploring new strategies to surmount the failures in cancer treatment appears to be an unavoidable pursuit. Among these strategies, immunology-based ones hold substantial promise in combatting cancer and immune-related disorders. A particular subset of this approach identifies "eat me" and "Don't eat me" signals in cancer cells, contrasting them with their counterparts in non-cancerous cells. This distinction could potentially mark a significant breakthrough in treating diverse cancers. By delving into signal transduction and engineering novel technologies that utilize distinct "eat me" and "Don't eat me" signals, a valuable avenue may emerge for advancing cancer treatment methodologies. Macrophages, functioning as vital components of the immune system, regulate metabolic equilibrium, manage inflammatory disorders, oversee fibrosis, and aid in the repair of injuries. However, in the context of tumor cells, the overexpression of "Don't eat me" signals like CD47, PD-L1, and beta-2 microglobulin (B2M), an anti-phagocytic subunit of the primary histocompatibility complex class I, enables these cells to evade macrophages and proliferate uncontrollably. Conversely, the presentation of an "eat me" signal, such as Phosphatidylserine (PS), along with alterations in charge and glycosylation patterns on the cellular surface, modifications in intercellular adhesion molecule-1 (ICAM-1) epitopes, and the exposure of Calreticulin and PS on the outer layer of the plasma membrane represent universally observed changes on the surface of apoptotic cells, preventing phagocytosis from causing harm to adjacent non-tumoral cells. The current review provides insight into how signaling pathways and immune cells either stimulate or obstruct these signals, aiming to address challenges that may arise in future immunotherapy research. A potential solution lies in combination therapies targeting the "eat me" and "Don't eat me" signals in conjunction with other targeted therapeutic approaches. This innovative strategy holds promise as a novel avenue for the future treatment of cancer.

Dataset Information

New hope for tumor immunotherapy: the macrophage-related "do not eat me" signaling pathway.

Publications

New hope for tumor immunotherapy: the macrophage-related "do not eat me" signaling pathway.

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