Targeting CD24/Siglec-10 signal pathway for cancer immunotherapy: recent advances and future directions

Abstract

The small, heavily glycosylated protein CD24 is primarily expressed by many immune cells and is highly expressed mostly in cancer cells. As one of the most crucial biomarkers of cancers, CD24 is frequently highly expressed in solid tumors, while tumor-associated macrophages express Siglec-10 at high levels, Siglec-10 and CD24 can interact on innate immune cells to lessen inflammatory responses to a variety of disorders. Inhibiting inflammation brought on by SHP-1 and/or SHP-2 phosphatases as well as cell phagocytosis by macrophages, the binding of CD24 to Siglec-10 can prevent toll-like receptor-mediated inflammation. Targeted immunotherapy with immune checkpoint inhibitors (ICI) has lately gained popularity as one of the best ways to treat different tumors. CD24 is a prominent innate immune checkpoint that may be a useful target for cancer immunotherapy. In recent years, numerous CD24/Siglec-10-related research studies have made tremendous progress. This study discusses the characteristics and workings of CD24/Siglec-10-targeted immunotherapy and offers a summary of current advances in CD24/Siglec-10-related immunotherapy research for cancer. We then suggested potential directions for CD24-targeted immunotherapy, basing our speculation mostly on the results of recent preclinical and clinical trials.

Enhancing anticancer activity of macrophages through rational drug combinations

“…Unfortunately, clinical trial results have so far been suboptimal owing to limited drug response duration and accrued toxicity ( 8 ). Anti-CD24 antibodies that block the interaction with its ligand Siglec-10, expressed on macrophages and other innate immune cells, increase phagocytosis of cancer cells by macrophages, with encouraging results in early-phase clinical trials ( 9 , 10 ). Indeed, ClinicalTrials.gov lists more than 20 trials as completed or underway that explore the clinical utility of targeting CD47 and CD24, with most of these being monotherapy.…”

Checkpoint CD24 function on tumor and immunotherapy

“…Although CD24 does not have any secondary structure, it is expressed on the surface of various cell types, including hematopoietic cells (such as T cells, B cells, myeloid cells, dendritic cells, and macrophages) and non-hematopoietic cells (such as keratinocytes, muscle fibers, neurons, renal tubular epithelial cells) ( 17 ).…”

From mechanism to therapy: the journey of CD24 in cancer

“…Recent studies elucidate the molecular pathways underpinning the CD24-Siglec-10 axis, highlighting its significance in immune tolerance and exploitation by cancer cells to evade immune surveillance (145)(146)(147). The blockade of this checkpoint has demonstrated potential therapeutic benefits, revealing a decrease in tumor growth and an increase in the efficacy of other immunotherapeutic strategies when the inhibitory effects of CD24 are neutralized (148).…”

“…Siglec-10 is a negative regulator of immune responses, and it has been shown to interact with CD24 on dendritic cells and B cells to inhibit their activation (158,165,166). Interaction between CD24 and Siglec-10 effectively transmits a "don't eat me" signal, inhibiting the phagocytic activity of these immune cells against cancer cells (Figure 4) (145,172). Siglec-15 is another member of the Siglec family that has been also shown to interact with CD24.…”

“…These interactions result in the phosphorylation of SHP-1/2 (Src homology region 2-containing protein tyrosine phosphatases) within the macrophage, leading to an inhibitory signal transduction that prevents phagocytosis. Consequently, the cancer cell evades immune destruction and proliferates (145,150). The lower half of the figure represents a potential therapeutic strategy to subvert this immune evasion.…”