Emerging Immune Checkpoint Molecules on Cancer Cells: CD24 and CD200

Abstract

Cancer immunotherapy strategies are based on the utilization of immune checkpoint inhibitors to instigate an antitumor immune response. The efficacy of immune checkpoint blockade, directed at adaptive immune checkpoints, has been demonstrated in select cancer types. However, only a limited subset of patients has exhibited definitive outcomes characterized by a sustained response after discontinuation of therapy. Recent investigations have highlighted the significance of immune checkpoint molecules that are overexpressed in cancer cells and inhibit myeloid lineage immune cells within a tumor microenvironment. These checkpoints are identified as potential targets for anticancer immune responses. Notably, the immune checkpoint molecules CD24 and CD200 have garnered attention owing to their involvement in tumor immune evasion. CD24 and CD200 are overexpressed across diverse cancer types and serve as signaling checkpoints by engaging their respective receptors, Siglec-10 and CD200 receptor, which are expressed on tumor-associated myeloid cells. In this review, we summarized and discussed the latest advancements and insights into CD24 and CD200 as emergent immune checkpoint moieties, further delving into their therapeutic potentials for cancer treatment.

Keywords: CD200; CD200 receptor; CD24; Siglec-10; immune checkpoint molecules.

Figure 1

Interaction of CD47 on cancer cells with SIRPα on phagocytes. Innate immune checkpoint CD47–SIRPα axis can be targeted through multiple mechanisms (1–4) in the tumor microenvironment. 1. CD47–SIRPα binding induces the phosphorylation of two immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic tail of SIRPα. This leads to the recruitment and activation of phosphatases, including SHP1 and SHP2, ultimately resulting in the inhibition of cancer cell phagocytosis by macrophages. Anti-CD47 antibody or anti-SIRPα antibody induces the uptake of tumor cells by macrophages via blocking the interaction between “Don’t eat me” signal (CD47) and immune checkpoint receptor (SIRPα). 2. Anti-CD47 antibodies facilitate phagocytic absorption of cancer cells by dendritic cells. This triggers an anticancer adaptive immune response. 3. Anti-CD47 antibodies eradicate cancer cells via natural killer antibody-dependent, cell-mediated cytotoxicity. ADCC: antibody-dependent, cell-mediated cytotoxicity. 4. Anti-CD47 antibodies induce apoptosis in cancer cells.

Figure 2

Interaction between CD24 on cancer cells and Siglec-10 on immune macrophages. The binding of CD24 to Siglec-10 induces Src kinases through ITIM and ITIM-like motifs, leading to the phosphorylation of ITIM tyrosine and the recruitment of tyrosine phosphatases (SHP1 and SHP2). These inhibitory signaling cascades block cytoskeletal rearrangement and inflammatory signaling. Blocking the CD24–Siglec-10 axis using anti-CD24 or anti-Siglec-10 antibodies induces phagocytosis and proinflammation in macrophages.

Figure 3

The interaction of CD200 in cancer cells and CD200 receptor in immune cells. CD200 preliminary engages with its CD200 receptor (CD200R), leading to the suppression of immune cell function and activation by inhibiting RAS signaling. CD200–CD200R binding induces phosphorylation of the tyrosine motif in the cytoplasmic tail of CD200R. The adaptor protein tyrosine kinase 2 (DOK-2) is then phosphorylated as a result. Subsequently, this leads to the binding of SH2-containing inositol phosphatase (SHIP) to DOK-2 and the recruitment of Ras GTPase-activating protein (RasGAP). RasGAP inhibits the Ras–MAPK pathway by facilitating GTP hydrolysis from RasGTP to Ras GDP. The RAS signaling pathway further induces the transcription of proinflammatory cytokines. Anti-CD200 antibody or anti-CD200R antibody induces proinflammation by immune cells.