CD28:a pro-survival signaling molecule in multiple myeloma as a novel therapeutic target (P2029)

Abstract

Abstract Multiple myeloma (MM) survival is dependent on the bone marrow microenvironment and is mediated by the receptor CD28, expressed on MM cells. CD28 expression correlates clinically with poor outcomes, and we have shown that CD28 signaling protects MM from chemotherapy. However, the molecular pathway by which CD28 does this is not clear. Since CD28 signals via a PI3K-Akt-FoxO3a axis in T cells, we interrogated whether this pathway is critical in MM. We observed that blockade of PI3K or Akt abrogates CD28-mediated survival. Upon CD28 activation, transcription factor FoxO3a is phosphorylated and excluded from the nucleus. Being downstream of FoxO3a, we examined whether the pro-apoptotic molecule Bim is regulated by CD28. Indeed, CD28 activation downregulates Bim, blockade upregulates it, and Bim silencing abrogates sensitivity to CD28 blockade. To confirm that stromal cells protect MM, we cocultured MM and dendritic cells and observed increased survival. However, if CD28 or CD80/86 is blocked, protection is completely abrogated. To examine if this is relevant in vivo, we used the murine myeloma model Vk*MYC and a SCID/human model. In either case, treatment with CTLA4-Ig (to block CD80/86) in combination with a sub-therapeutic chemotherapy dose was able to significantly decrease tumor burden and extend survival. Taken together, these data suggest that CD28 is a direct mediator of chemotherapy resistance in vivo, and blockade of CD28 represents a novel target for clinical therapy.