Elotuzumab Enhances the Th2-Mediated Immune Response of Dendritic Cell Induced By Immunomodulatory Drugs (IMiDs)
Authors: Azuma Yoshiko , Ito Tomoki , Inaba Muneo , Imai Kai , Hotta Masaaki , Satake Atsushi , Nomura Shosaku 
Published: November 2019

Background: Elotuzumab, a humanized IgG1 monoclonal antibody targeting SLAMF7, is useful for the treatment of Relapsed or Refractory multiple myeloma (RRMM) in combination with Lenalidomide (LEN). However, cellular and molecular mechanisms underlying the immunomodulatory effects of elotuzumab still remain largely unclear. We have previously reported that LEN displays immunopotentiating activity that enhances Th2-mediated response at dendritic cell (DC) phase as upstream immune cascade associated with humoral immunity. DCs are pivotal cells in the sense of orchestrating both cell-mediated (linking with Th1) and humoral (linking with Th2) immunity as masters of the immune system. Series of analyses have clarified myeloid DCs (mDCs) play an important role in allergic immune response by the induction of Th2 response. Here, we focused on the effects of elotuzumab in combination with LEN on the function of human mDCs.
Methods: Purified blood human CD11+ mDCs from healthy adult volunteers using cell sorting were cultured and analyzed by flow cytometry and ELISA. Serum were obtained from 16 MM patients with before and after elotuzumab therapy. This study was approved by the Institutional Review Board of Kansai Medical University.
Results: We found that surface expression of SLAMF7 on mDCs was upregulated in response to Th2-inducing cytokine, thymic stromal lymphopoietin (TSLP) and the expression level was higher in response to TSLP than in response to toll-like receptor ligand R848. Elotuzumab at clinical in vivo plasma concentration of 30 to 300 µg/ml did not affect mDC survival and their CD86 and OX40-ligand expression when stimulated with 0.3 µM LEN and/or TSLP for 24 h. LEN enhanced TSLP-mediated Th2-recruiting chemokine CCL17/TARC from mDCs which functions as chemoattractant for memory Th2 cells and contribute to allergy and humoral immune responses, and elotuzumab significantly enhanced the LEN-mediated production of CCL17/TARC (TSLP+LEN as control vs. TSLP+LEN+100 µg/ml elotuzumab; 1.23 fold increase: p=0.003, and control vs. TSLP+LEN+300 µg/ml elotuzumab; 1.38 fold increase: p=0.038). This finding suggest elotuzumab enhances Th2-mediated immune profile at upstream phase of humoral immunity. In addition, serum CCL17 levels were analyzed in RRMM patients before and after 3 cycle elotuzumab administration (n=16). We found, serum CCL17 levels after elotuzumab administration were significantly higher compared with those before elotuzumab treatment (after; 1512 ± 459 pg/ml vs. before; 402.2 ± 87.4 pg/ml: p = 0.013).
Conclusion: MM involves an element of humoral immune dysfunction. Immune status is important for the prognosis of MM, and clinical outcome can be improved by the recovery of immune status. In this context, our data showing the enhancement of Th2-mediated response by elotuzumab provide a plausible explanation for the observed clinical benefit of this antibody-drug in MM. This function of elotuzumab seems to be relevant to the treatment of MM patients under humoral immune dysfunction. Based on our data in focusing on DCs in the immune system, elotuzumab and IMiDs could function as immunostimulators of humoral immunity via mDCs, and this finding elucidated an additional cellular target of elotuzumab.

Disclosures
Ito: Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding.