The Many Facets of CD38 in Lymphoma: From Tumor-Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy

Abstract

The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In chronic lymphocytic leukemia, the prognostic significance of CD38 expression is well accepted, and preclinical studies on the use of Daratumumab in monotherapy or combination therapy have demonstrated considerable efficacy. In other lymphoproliferative disorders, preclinical and clinical data have not been as compelling; however, CD38 overexpression likely contributes to resistance to checkpoint inhibitors, prompting numerous clinical trials in Hodgkin and non-Hodgkin lymphoma to investigate whether blocking CD38 enhances the efficacy of checkpoint inhibitors. Furthermore, due to its widespread expression in hematological tumors, CD38 represents an attractive target for cellular therapies such as CAR-T cells. The present review discusses current knowledge of CD38 expression and its implications in various lymphoid malignancies. Furthermore, it addresses current and future therapeutic perspectives, with a particular emphasis on the significance of CD38 interaction with immune cells of the tumor microenvironment. Lastly, results of ongoing studies using anti-CD38 antibodies will be reviewed.

Keywords: CD38; Daratumumab; checkpoint inhibitors; immunoescape; lymphoma.

Figure 1

Creation of immunosuppressive microenvironment by CD38-expressing immune cells. The activation of CD38-mediated signaling pathways on regulatory T cells, regulatory B cells, MDSCs and specific NK cell subsets of the tumor microenvironment leads to inhibition of effector T-cell activity, thus contributing to immune escape.

Figure 2

CD38-mediated acquired resistance to PD-1/PD-L1 Inhibitors. Malignant cells resistant to checkpoint inhibition produce mediators such as ATR that lead to CD38 up-regulation via RARα. CD38 catalyzes the conversion of NAD⁺ into immunosuppressive adenosine via the CD38/CD203a/CD73 ectoenzymatic pathway. Adenosine interacts with A2AR and A2BR adenosine receptors on CD8⁺ T cells, thus suppressing cytotoxic activity.