(PA-267) Tumor-immune Microenvironment Interaction Drives the Co-evolution of Multiple Myeloma and Immune Cells in a Novel Mouse Model Engineered with Human Immune System

A variety of pre-clinical mouse models have been established to recapitulate different biological features of multiple myeloma(MM). Depending on the need of the studies, the mice that were used are either immunocompromised (NSG/SCID) or immunocompetent (syngenic/transgenic) with the immune system of the mice. Both models, however, do not truly mimic the immunological feature in MM patients and thus, may not be translationally relevant for the interrogation of MM-immune-microenvironment interaction. We aim to address this deficiency by generating an immunocompetent mouse model, i.e. mice that are humanized with human immune system (humice). We have previously shown its efficacy for MM engraftment and that MM cells grown in humice possess different molecular profile compared to them in non-humice NSG. Here, we decipher how tumor-immune interaction in humice affects the integrity of the immune system and MM responsiveness to immunotherapies.

 

Methods:   

U266-Luc-GFP cells were inoculated into the humice, via teil vein and tumor growth was monitored with bioluminescence imaging. Upon reaching desired tumor burden, we randomized the xenografts into three treatment arms (n=6); (a)vehicle (b)teclistamab (c)lenalidomide. Serial withdrawal of PBMCs was performed on MM-engrafted (MM-humice) and -non-engrafted humice (non-MM-humice) once every fortnightly for immune profiling via flow cytometry.

 

Results:   

In tumor-free condition, the non-MM humice demonstrated a stable profile for all the principle immune components, namely the CD3+ T cells, CD19+ B cells, CD56+ NK cells and CD14+ monocytes, suggesting an unperturbed immune system without tumor stimulation or immune-tumor interaction. CD138 expression in the PBMC showed a gradual increase in the MM-humice, whereas its expression remains low in the non-MM-humice, suggesting the presence of circulating malignant plasma cells in the humice and how human immune microenvironment in vivo could support MM growth. This was accompanied by a complex mixture of other immune phenotypes; CD3+ T cells showed a gradual increase in cell population, in tandem with the immune checkpoint PD1 protein. CD19+ B cell population was declining, whereas CD56+ NK cells and CD14+ monocytes displayed a delayed surge in its abundance. While the T helper cell (CD4+,T_h) population remain stable, its cytotoxic counterpart (CD8+,T_c) experienced a progressive increase. There was also a fluctuation of naïve (CD45RO+) and memory (CD45RA+) T_h and T_c. Teclistamab showed greater efficacy than lenalidomide, associated with enriched T_c and NK cells.

 

Conclusions:   

We showed that, in our humice, immune cells undergo physiological alterations when exposed to MM cells, suggesting that immune integrity may be affected by immune-tumor interaction. The complex immune profile also replicates the immune heterogeneity observed in the patients.  Our data therefore supports the use of these humice as a translationally relevant model for studying immune-tumor interactions and testing immunotherapies.