Abstract
Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate decreased CD4+ Th cells, increased Treg and G-type MDSC, and upregulation of immune checkpoints on effector/regulatory and CD138+ cells in MM patients, compared MGUS/SMM patients or healthy individuals. Among the checkpoints profiled, LAG3 was most highly expressed on proliferating CD4+ Th and CD8+ Tc cells in MM patients BMMC and PBMC. Treatment with antibody targeting LAG3 significantly enhanced T cells proliferation and activities against MM. XBP1/CD138/CS1-specific CTL generated in vitro displayed anti-MM activity, which was further enhanced following anti-LAG3 treatment, within the antigen-specific memory T cells. Treg and G-type MDSC weakly express LAG3 and were minimally impacted by anti-LAG3. CD138+ MM cells express GAL-3, a ligand for LAG3, and anti-GAL-3 treatment increased MM-specific responses, as observed for anti-LAG3. Finally, we demonstrate checkpoint inhibitor treatment evokes non-targeted checkpoints as a cause of resistance and propose combination therapeutic strategies to overcome this resistance. These studies identify and validate blockade of LAG3/GAL-3, alone or in combination with immune strategies including XBP1/CD138/CS1 multipeptide vaccination, to enhance anti-tumor responses and improve patient outcome in MM.
Highlights
Despite major improvements in the treatment of multiple myeloma (MM), novel agents targeting the tumor and its microenvironment are urgently needed
The tumor lysates induced a greater T-cell response in MM patients’ BMMC (N = 5) than irradiated whole tumor cells, which was enhanced to a greater extent by checkpoint inhibitors than by immune agonists (Supplementary Fig. 1)
We showed that G-type Myeloidderived suppressor cells (MDSC) (CD11b+ CD33+ HLA-DRlow/− CD14− CD15+), but not M-type MDSC (CD11b+ CD33+ HLA-DRlow/− CD14+ CD15−), are significantly (*p < 0.05) increased in BMMC of MM patients compared to monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) patients or healthy donors (Fig. 3A)
Summary
Despite major improvements in the treatment of multiple myeloma (MM), novel agents targeting the tumor and its microenvironment are urgently needed. In preclinical and clinical studies, we reported that XBP1/CD138/CS1 multipeptide can induce antigen-specific memory CTL against MM [14,15,16,17,18], and that this therapeutic approach when combined with optimal immune modulators may further overcome immunosuppression characteristic of MM [19, 20]. LAG3/GAL-3 blockade can efficiently enhance the proliferation of T cells in MM patients and functional activities of MM-specific CTL, including XBP1/CD138/CS1-targeting memory CD8+ T cells, against MM These studies provide the rationale for inhibiting LAG3/GAL-3, in combination with immunotherapy including a cancer vaccine, to overcome the immune suppressive tumor microenvironment, enhance anti-tumor-specific immune responses, and improve patient outcome in MM
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