Dr Van Oekelen on the Role of S100A8/A9 in Promoting T-Cell Exhaustion in Multiple Myeloma

“Here we showed that the level of S100A8/A9 was significantly higher in patients who didn’t achieve a very good partial response, so the patients had a poor response at higher levels. We also showed that that correlated with poor progression-free survival.”

Oliver Van Oekelen, MD, PhD, an internal medicine and medical oncology resident at the Icahn School of Medicine at Mount Sinai, discussed findings on the role of S100A8/A9 in promoting T-cell exhaustion and limiting responses to bispecific antibody therapy in multiple myeloma. The investigation, which included both patient sample analysis and in vitro assay evaluation, provided mechanistic insights into resistance biology and highlighted a potential therapeutic target to enhance T-cell–directed immunotherapies.

In the first part of the study, investigators evaluated serum levels of S100A8/A9 in approximately 20 patients treated with bispecific antibodies targeting either BCMA or GPRC5D. The analysis revealed that patients with elevated baseline or on-treatment S100A8/A9 levels were less likely to achieve a very good partial response or better. Higher serum concentrations also correlated with inferior progression-free survival, suggesting that S100A8/A9 may serve as a prognostic marker.

The second component of the study involved functional in vitro studies to assess the effect of S100A8/A9 on T-cell phenotype and activity. T cells exposed to elevated concentrations of S100A8/A9 demonstrated features of exhaustion, including reduced cytokine production and diminished cytotoxic activity against myeloma cell lines that were co-cultured with bispecific antibodies. These findings indicate that the immunosuppressive effect of S100A8/A9 directly impairs T-cell function.

Importantly, preclinical models incorporating a monoclonal antibody targeting S100A8/A9 reversed many of these effects. Blocking S100A8/A9 restored T-cell function, improving cytokine production and cytotoxic capacity in the presence of bispecific antibodies. These results provide proof of concept that therapeutic strategies directed at S100A8/A9 could mitigate T-cell exhaustion and enhance the activity of bispecific antibody therapies in multiple myeloma. Van Oekelen emphasized that these findings underscore the role of S100A8/A9 as a potential biomarker of resistance to T-cell–redirecting therapies.

Disclosures: Van Oekelen reported no disclosures.