Date of Award
Doctor of Philosophy (PhD)
Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematologic malignancy in the world. Despite an array of novel therapy approvals, MM remains to be incurable. Most patients ultimately relapse and become refractory to previous treatments, which lowers the median survival to only 5–15 months. Recently, cancer immunotherapy has gained attention as a promising approach to enhance the body’s natural immune responses to fight cancer. Currently, immunotherapies in MM have largely focused on engaging the T cells; however, many are challenged by insufficient responses, high cost, and/or extensive adverse effects. Thus, alternative methods are warranted to elicit immune activation against myeloma. Macrophages are central players in the innate immune system with diverse functions, and it has been long established that macrophages play a critical role in both inducing direct and indirect immune responses in cancer. Unlike T cells, macrophages are able to recognize pathogens directly and react much faster to inhibit or kill cancer cells, and further confer sustained adaptive immune responses. However, under the influence of the immunosuppressive tumor microenvironment (TME), cancer cells have developed numerous mechanisms to avoid macrophage recognition, even to the extent of recruiting and educating macrophages to work in their favor. In this dissertation, I present two strategies to activate macrophage immune response and enhance macrophage killing of MM. First, we aimed to enhance macrophage recognition of MM by blocking CD47, a surface protein that cancer cells present to evade macrophage surveillance and phagocytosis. We hypothesized that blocking CD47 on MM cells will enhance macrophage mediated phagocytosis and killing of MM. To address this hypothesis, we evaluated the relevance of CD47 in MM patients, explored the effect of the TME on CD47 expression, and determined the effect of CD47 inhibition on MM killing in a 3D tissue-engineered BM model. We found that CD47 expression on MM cells correlated with disease progression and were 8-fold higher compared to other leukocytes in the BM. Further, anti-CD47 monoclonal antibody (mAb) treatment elicited significant killing of MM that was mediated by macrophages. Importantly, we demonstrated the importance of drug investigation in a 3D culture environment compared to the traditional 2D environment. Secondly, we aimed to reprogram tumor-associated macrophages (TAMs) to reverse their support on MM survival and drug resistance. TAMs are a special population of macrophages residing in the TME that exhibit tumor-supporting characteristics. We hypothesized that MM secreted IL-10 cytokines polarize TAMs toward the pro-tumor M2 phenotype, and that inhibition of IL-10/IL-10R pathway on TAMs will reverse their M2 phenotype and re-sensitize MM to treatment. We found that TAMs in patients and in MM inoculated mice presented significantly heightened M2 phenotype compared to healthy controls. Inhibition of IL-10R with blocking mAbs robustly reversed M2 phenotype in vitro, ex vivo, and in vivo. Furthermore, IL-10R inhibition resulted in TAM mediated killing of MM, and further enhanced traditional anti-MM therapies by reversing TAM-supported drug resistance. In summary, this thesis dissertation investigated two mechanisms in which MM-associated macrophages participate in immunosuppression, and developed novel strategies targeting the two mechanisms. Our findings provided a better understanding of the factors that drive macrophage- mediated immunosuppression, and provided us with insights toward possible macrophage-targeted approaches to overcome immunosuppression. Further studies are warranted to explore these strategies as combination with current anti-MM regimens to induce a thorough and effective elimination of MM, providing sustained treatment options for MM patients.
Abdel Kareem Azab
Available for download on Thursday, December 28, 2023