Targeting CD38 alleviates tumor-induced immunosuppression

Targeting CD38, a common blood cell membrane receptor highly expressed on many Band T-cell cancers, has achieved significant clinical activity with an acceptable safety profile in multiple myeloma (MM). Specifically, daratumumab (dara) was the first naked CD38 monoclonal antibody (mAb) approved for the treatment of relapsed and refractory MM (RRMM) in 2015. Importantly, it induces high response rates in two phase III trials in RRMM when combined with bortezomib or lenalidomide plus dexamethasone [1]. Due to its efficacy and lack of toxicity, naked CD38 monoclonal antibody has great promise, either as a single agent or in combination, in other hematological malignancies as well. Isatuximab (Isa), a novel humanized IgG1-kappa CD38 mAb targeting a completely different epitope in CD38 molecule than dara, achieves significant responses when combined with lenalidomide and dexamethasone in heavily pretreated patients with RRMM [2]. Isa, like dara, induces MM cell lysis via multiple effector cell-dependent mechanisms including antibody-dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), and antibody-dependent phagocytosis (ADCP). In contrast to dara, isa directly kills MM cells via lysosomemediated cell death and apoptosis in the absence of Fc cross-linking agents or effector cells [3]. Furthermore, this direct toxicity is preferentially seen in myeloma cells expressing elevated levels of CD38 regardless of p53 mutations, which are common in the setting of RRMM. Since CD38 is widely expressed on hematopoietic cells, it is crucial to study how isa impacts on various CD38-expressing subsets to influence clinical responses. We recently defined the effects of isa on myelomasupporting osteoclasts (OCs) and immune cell subsets in the bone marrow microenvironment [4, 5]. Besides directly promoting MM cell growth and survival in the bone marrow (BM) microenvironment, OCs protect MM cells against T-cell-mediated cytotoxicity via direct inhibition of proliferating CD4+ and CD8+ T cells [4]. We first found that CD38 is upregulated during osteoclastogenesis, and that isa has limited direct cytotoxicity against OCs. Importantly, isa alleviates suppression of T cell function by OCs, along with downregulation of the immune checkpoint molecule herpesvirus entry mediator (HVEM) and the T-cell metabolism regulator indoleamine 2, 3-dioxygenase (IDO). Therefore, isa may enhance immunotherapeutic activity and mitigate bone disease by restoring T-cell function. Next, we identified significantly increased CD38 levels on the cell membrane of regulatory T cells (Tregs) (CD4+CD25highFoxp3+) when compared with conventional T effector cells (Tcons, CD4+CD25-) [5]. Elevated CD38 expression and CD38high subsets are defined in Tregs versus Tcons, associated with significantly enhanced CD38 targeting by isa on Treg vs Tcon. As seen in CD38high MM cells, isa preferentially targets Tregs vs Tcon via triggering apoptosis and decreasing proliferation (Figure 1). Furthermore, low dose (1μM) lenalidomide and pomalidomide significantly increase CD38 level on viable Tregs and percentages of CD38high Tregs in culture. These results suggest that IMiDs can enhance the sensitivity of viable Tregs to Isa, resulting in enhanced NKand CD8+ T effector cell-mediated anti-tumor immune responses. Importantly, CD38high subsets are increased on Tregs of MM patients vs normal donors. We found that MM cells can convert Tcon into Tregs in ex vivo co-cultures. These iTregs can be induced by cell-to-cell contact-dependent and -independent interactions between myeloma cells and Tcons, mimicking increased Tregs in MM patients vs normal donors. These iTregs show significantly elevated CD38 and Foxp3 levels when compared with Tcons. They still significantly decrease proliferation of Tcons, which is overcome by isa. Levels of CD38 correlate with Foxp3 Editorial