CD300 Molecules May Be Influential Immune Regulators, Therapy Targets in AML

Finding therapeutic targets for acute myeloid leukemia (AML) has proven challenging, but a set of immune-regulating molecules may hold promise as biomarkers and targets.

Certain proteins in the CD300s group of molecules—which are known to have roles in immune response—are typically overexpressed in cancerous tumors, and especially in acute myeloid leukemia (AML), according to a recent study published in Cancer Medicine. CD300s may therefore hold potential as prognostic biomarkers and immunotherapy targets in patients with AML, the investigators determined.

Currently, the standard of care for AML is chemotherapy, but most patients relapse and survival rates are low. AML has not shown the robust response that some cancer types have displayed with currently approved immune checkpoint inhibitors, although studies on co-inhibitory molecules with potential in AML are ongoing.

There are 7 members of the human CD300 receptor family: CD300A, CD300LB, CD300C, CD300LD, CD300E, CD300LF, and CD300LG. All are located on chromosome 17, and CD300A and CD300LF contain immunoreceptor tyrosine-based inhibitory motifs and therefore have an inhibitory-dominant role in immune processes. Myeloid cells—such as monocytes, macrophages, and dendritic cells—are main sites of CD300 molecule expression. CD300A specifically is expressed on natural killer (NK) and CD8+ T cells, both of which are tumor suppressive.

Only few studies have suggested CD300A is overexpressed in hematological cancers, the authors note. In the current study, they analyzed the role of CD300 molecules in the tumor microenvironment, expression patterns, transcriptional regulations, and their clinical impacts across cancers, with a particular interest in AML.

Of the 7 CD300 molecules, CD300A, CD300LB, CD300C, CD300LF, and CD300LG were included in the analysis. These 5 were present in a dataset of both healthy and AML samples from the Gene Expression Omnibus that was used to validate the differences in expression between normal and AML cells. Using the Genotype-Tissue Expression database, CD300A, CD300LB, CD300C, and CD300LF were found to be expressed mainly in blood, lung, and spleen tissue. CD300LG was principally expressed in adipose, breast, heart, and testis tissue, but not in blood. Overall, CD300LG had different transcriptional and clinical characteristics than CD300A-CD300LF.

Although CD300A-CD300LF were significantly overexpressed in AML in this analysis and were also often upregulated in tumors, CD300LG showed the opposite pattern. CD300A was found to have prognostic value in AML, with overexpression carrying a poorer prognosis. These findings were confirmed with 7 independent AML datasets and a meta dataset of 1115 patients with AML, and CD300A expression was useful in refining AML classification schemes in this study.

Immune cells with myeloid lineage showed high expressions of CD300A-CD300F, and the same molecules were elevated in monocyte-like subsets of AML. NK cells infiltrating AML cells had high CD300A expression, and the authors suggest that CD300A may inhibit the NK cells’ cytotoxicity and allow AML cells to escape immune response.

“We can safely speculate that blocking CD300A could restore NK cells’ activity and lead to AML suppression,” the authors wrote. “Accordingly, we found CD300A expression was positively correlated with T-cell dysfunction score and high CD300A expressers were predicted to have a better response to immunotherapy in AML.”

The study was limited due to a lack of data on CD300LD and CD300E expression, and the authors noted that previous data suggest CD300A as a significant prognostication tool. Experiment-based research and clinical trial assessments are also warranted to supplement the bioinformatics analyses performed for this study. However, the findings further confirmed the prognostic value of CD300A with a more robust confirmatory cohort and provided insight on the behavior of CD300s in other cancer types.

Reference

Xu ZJ, Jin Y, Zhang XL, et al. Pan-cancer analysis identifies CD300 molecules as potential immune regulators and promising therapeutic targets in acute myeloid leukemia. Cancer Med. Published online May 31, 2022. doi:10.1002/cam4.4905