Activated cDCs by aCD40 therapy induce anti-tumor effects in Multiple Myeloma

Multiple Myeloma (MM) is the second most common hematological malignancy, typically associated with a disturbed immune surveillance. Although the development of immunotherapies has prolonged the survival rate in MM, patients often relapse. Therefore, a thorough understanding of immune subtypes during MM progression is still needed to develop novel, and improve the current therapeutic approaches.
We aimed to fully map the immune cell compartment within the tumor microenvironment (TME) of the immunocompetent 5T33MM mouse model. At distinct stages of disease progression, we assessed the heterogeneity and activation status of key players in mounting an anti-tumor immune response being; the DC and T-cell compartment.
Single cell RNA-sequencing and flow cytometry data revealed the presence of cDC subsets within the TME. However, the expression level of activation markers decreased upon MM disease progression, suggesting a less activated DC profile in MM-bearing mice. Interestingly, despite the increased proportion of effector memory T cells in the TME, they are unable to control tumor growth. Therefore, we aimed to stimulate DC activation by using aCD40 therapy in vivo. aCD40 therapy significantly increased the activation status of cDCs, which was accompanied with an increase in CCR7+ cDCs. Moreover, we observed an increase in the proportion of effector memory T cells in the TME, which resulted in a significant drop in tumor load.
We believe our findings demonstrate the overlooked importance of cDCs in anti-MM responses, as we provide the first preclinical evidence that in vivo activated cDCs by aCD40 therapy could increase effector immune responses, resulting in a significant decrease in tumor load.