Cellular immunotherapy can induce long term remissions in multiple myeloma (MM) patients. Despite reported successes in a limited number of patients, the immune system fails to completely eradicate MM in the majority, proving the ability of MM cells to evade cellular immunity. The nature and mechanism of this immune escape remains not fully understood. Most studies have focused on mechanisms by which tumor cells down-regulate their antigenicity or suppress immune effector cells. Here we show a critical role for the tumor microenvironment in inducing a cell-adhesion mediated ability in MM cells to resist T cell mediated killing; a mechanism similar to cell-adhesion mediated drug resistance (CAM-DR).
We used a compartment-specific bioluminescence-based viability assay, in which luciferase transduced MM cell lines were co-cultured with MM-reactive CD4+ and CD8+cytotoxic T cells (CTLs) in presence and absence of accessory cells. In these co-culture assays, we demonstrated the effective CTL-mediated lysis of MM cells. However, this lysis was significantly decreased in the presence of accessory cells, such as bone marrow stromal cells, including patient derived stromal cells, activated endothelial cells and fibroblasts.
We identified that the reduction of CTL-mediated lysis was predominantly due to the induction of a cell-cell contact mediated resistance in MM cells against CTL killing, proving for the first time the existence of a cell-adhesion mediated immune resistance (CAM-IR). In support to this, blocking the adhesion of MM cells to accessory cells with an ICAM-1 antibody or with RGD peptide, which is a ligand for cell surface integrins, abrogated the resistance of MM cells against CTL-mediated lysis. Intracellular mechanisms of this immune resistance were evaluated by western blot. Adherence of MM cells to accessory cells significantly increase the expression levels of survivin in MM cells, a well known inhibitor of apoptosis protein (IAP), which blocks the CTL mediated apoptotic events via inhibiting the phosphorylation of caspase-3. Our current focus is the restoration of MM cell sensitivity to T cell mediated killing via downregulation of survivin expression.
In conclusion, we report for the first time the potentially important role of microenvironment in compromising immunotherapy by the induction of CAM-IR. Our results suggest that immunotherapy may be improved by modulating the interaction of MM with its microenvironment
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.