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Department of Dermatology and Venereology, University Hospital Centre (CHUV) and University of Lausanne (UNIL), Lausanne, SwitzerlandDepartment of Immunology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandDepartment of Dermatology, Hospital 12 de Octubre, Medical School, University Complutense, Madrid, Spain
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphomas with primary skin manifestations and challenging diagnosis and treatment.
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A new study by Ta et. al. reports on high CD38 expression levels in skin lesions of a subpopulation of advanced aggressive CTCLs.
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The high expression levels of CD38 negatively correlate with the overall survival of patients with CTCL, providing a potential new prognostic marker.
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Ta et al. provide promising first observations on the therapeutic targeting of CD38 in a subgroup of advanced refractory CTCL.
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphomas manifesting in the skin for which effective treatment remains challenging. Immunophenotypic abnormalities are characteristic of neoplastic T cells. Loss of T-cell surface markers, such as CD2, CD3, CD4, CD5, CD7, or CD26; the presence of a monoclonal TCR population in the blood; or the presence of chromosomally abnormal T cells is common. Overexpression of molecules such as CCR4, CD30, PD-1, KIR3DL2, TIGIT, CD164, and T-plastin and Twist has been reported in CTCL, useful in the diagnostic workup and/or highly relevant for the development of successful disease-specific targeted therapies (
characterize the expression of CD38 in the skin, blood, and lymph nodes of a cohort of 67 patients with CTCL and report it as a potential treatment target for refractory advanced CTCL.
Versatile immunomodulatory roles of CD38
In humans, CD38 expression has been observed in the blood, bone marrow, and lymph nodes but also in the brain, retinal tubes, pancreatic islet astrocytes, prostate, white adipose tissue, liver, spleen, kidney, gut, and smooth muscle cells (Figure 1a) (
). Thus far, the most abundant CD38 expression has been found on immune cells, such as lymphocytes, plasma cells, NK cells, macrophages, monocytes, neutrophils, innate lymphoid cells, and myeloid and dendritic cells (DCs). CD38 is a multifunctional ectoenzyme and a signaling receptor, showing both adenosine diphosphate (ADP)-ribosyl cyclase and cyclic ADP-ribose hydrolase activities. Therefore, CD38 regulates nicotinamide adenine dinucleotide (NAD+) metabolism and maintains calcium homeostasis and signaling for both intracellular and extracellular compartments (
) (Figure 1b). Within a cell, CD38 can be located on the cell surface, in the cytosol, or in the intracellular compartments, including the nuclear membrane, endoplasmic reticulum, and mitochondria (
Figure 1Multifaceted molecule CD38. (a) CD38 is an omnipresent protein but is more abundant in hematopoietic tissues. (b) Multiple functions of CD38 are shown. CD38 is expressed predominately on immune cells and contributes through cADP- and NAADP-induced Ca2+ signaling to diverse immunoregulatory procedures, including cytokines release, cell recruitment, transendothelial migration (through interaction with CD31), antigen uptake and presentation, and phagocytosis. In the tumor microenvironment, CD38 promotes tumorigenesis and immunosuppressive effect and suppresses cell death program mediating resistance to cancer immunotherapy. (c) Among all listed immune-based therapeutic approaches for the treatment of CTCLs, CD38-targeting mAb isatuximab restraints immunosuppressive tumor microenvironment and induces ADCC, CDC, and ADCP by inhibiting the proliferation of Treg cells high-expressing CD38 and stimulating Treg apoptosis, thereby reducing the inhibition of NK and CD8+ effector cells by upregulating degranulation and IFN-γ production. Moreover, isatuximab can directly activate tumor cell apoptosis in the absence of effector cells. ab, antibody; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent phagocytosis; ADP, adenosine diphosphate; ADPR, adenosine diphosphate ribose; Ca2+, calcium ion; cADPR, cyclic adenosine diphosphate ribose; CDC, complement-dependent cytotoxicity; CTCL, cutaneous T-cell lymphoma; DC, dendritic cell; MZB, mogamulizumab; NAADP, nicotinic acid-adenine dinucleotide phosphate; NAD, nicotinamide adenine dinucleotide; STAT, signal transducer and activator of transcription; Treg, regulatory T cell; WAT, white adipose tissue.
combine flow cytometry, single-cell sequencing, and immunohistochemistry to decipher the expression of CD38 on neoplastic cells in blood and skin from patients with different CTCL subtypes. The study reveals predominant expression of CD38 in aggressive subtypes of CTCL, especially Sézary syndrome (SS) with large cell transformation and γ/δ- and NK/T-cell lymphomas. The expression level of CD38 correlated negatively with the overall survival too (
find that CD38int expression level on SCs was statistically higher than on normal CD8+ T cells from healthy donors (HDs) (no expression of CD38) but significantly lower than on normal CD4+ T cells from HDs and benign CD4+ T cells from patients with SS. Indeed, in an independent set of experiments, our group used Nanostring multiplex probe hybridization platform to study expression profiles in sorted neoplastic cells and benign cells from patients with SS and CD4+ T cells from HDs. The result of our independent experiments shows a lower expression level of CD38 on the SCs than those of benign T cells from patients with SS and CD4+ T cells from HDs, which is in line with the observations made by
and communicated in this recent article of the journal (Figure 2a). On the other side, the expression profile on formalin-fixed and paraffin-embedded skin tissues from patients with CTCLs or benign inflammatory skin disease atopic dermatitis (AD), performed by our group with the Nanostring technique, provides evidence that skin lesions from CTCLs expressed a higher level of CD38 than those from patients with benign inflammatory skin disease AD (Figure 2b). Similarly, the single-cell sequencing result performed by
showed a higher expression level of CD38 in CTCL skin lesions than in healthy skin and the predominant CD38+ cell subsets, including skin lymphocytes, macrophage/DCs, and keratinocytes. Moreover, the coexpression analysis based on single-cell sequencing data suggested that CD38 is coexpressed with multiple CTCL tumor cell markers, implying the expression of CD38 in CTCL tumor cells. Furthermore, the immunohistochemistry results showed a tendency of elevated expression of CD38 in skin biopsies from patients with CTCL with aggressive forms: 31% positive rate in aggressive subtypes (10 of 32) compare with 0% in indolent subtypes (0 of 17) (
Figure 2CD38 expression on circulated CD4+ T cells or skin lesions in patients with CTCLs. (a) Nanostring-based expression analysis showed the CD38 expression level on the sorted CD4+ T cells from HDs (n = 2) or patients with SS (n = 5). The result revealed a lower expression level of CD38 on the sorted Sézary cells in comparison with benign T cells from patients with SS and CD4+ T cells from HDs. (b) CD38 expression on the FFPE-embedded skin tissues from patients with benign skin disease AD (n = 3) or patients with CTCLs (n = 3). Skin lesions from CTCLs expressed a higher level of CD38 than those from benign inflammatory skin disease AD. (c) Flow cytometrical gating strategy for CD38 expression on neoplastic T cells of a representative patient with SS. (d) The mean CD38 expression on malignant T cells of patients with SS with bad prognosis (average disease duration of 3.3 [range = 1.2−5] years, n = 10) was significantly different from the mean CD38 expression on malignant T cells of patients with more favorable prognosis (average disease duration of 9.9 [range = 7−12] years, n = 10) expressed only low levels of CD38. (e) High expression of CD38 on malignant T cells of patients with SS correlated strongly with bad prognosis and short disease duration. AD, atopic dermatitis; Corr, correlation; CTCL, cutaneous T-cell lymphoma; FFPE, formalin-fixed paraffin-embedded; FSC, forward scatter; HD, healthy donor; SS, Sézary syndrome; SSC, side scatter
CD38 as a prognostic marker and therapeutic target
Several lines of evidence proposed CD38 as a prognostic marker in some pathologies. For instance, increasing levels of CD38+ plasma cells, T cells, and monocytes were shown in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus, suggesting the role of CD38 in the pathogenesis of these diseases. The treatment with daratumumab, a plasma cell−depleting anti-CD38 mAb, reduces RA progression and intensity of symptoms (
Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.
). CD38 is also implicated in neurodegeneration and neuroinflammation, supporting its role in multiple sclerosis progression.
Indeed, therapies with CD38 inhibitor activity, such as NAD+ analogs, flavonoids, and heterocyclic compounds, as well as anti-CD38 mAbs (daratumumab, isatuximab, TAK-079, and MOR202) have been proposed for the therapeutic target and have shown promising results in clinical and preclinical studies in the treatment of different autoimmune inflammatory diseases; hematologic malignancies; multiple myeloma; and solid tumors, including glioma, prostate adenocarcinoma, and breast cancer (
, the expression level of CD38 correlated negatively with the overall survival of patients with CTCL. In an independent retrospective study, our group applied routine flow cytometry to observe the CD38 expression in a cohort of 20 patients with SS (Figure 2c). Similar to that of
, our analysis clearly points out that the mean CD38 expression on malignant T cells of patients with SS with bad prognosis (average disease duration of 3.3 [range = 1.2−5] years, n = 10) was significantly higher than the mean CD38 expression on malignant T cells of patients with more favorable prognosis (average disease duration of 9.9 [range = 7−12] years, n = 10) (Figure 2d). The high expression of CD38 on malignant T cells of patients with SS patients correlated strongly with bad prognosis and short disease duration (Figure 2e). We believe that the analysis of the expression level of CD38 will help physicians to stratify patients into risk categories and therefore contribute to better treatment strategies.
’s results and ours synergistically point to CD38 as a potential prognostic marker and a new target for the treatment of aggressive and treatment-refractory CTCL.
Promising results of CD38-targeting therapy for aggressive refractory CTCLs
not only report the expression of CD38 in aggressive subtypes of CTCL but also uncover its steady expression on mogamulizumab and lacutamab treatment-resistant neoplastic cells. Ex vivo, the monoclonal anti-CD38 antibody isatuximab significantly facilitated antibody-dependent cell-mediated phagocytosis and antibody-dependent cellular cytotoxicity of neoplastic CTCL T cells. Even more, the flow cytometry readout from the study by
showed no expression of CD38 on CD8+ T cells, suggesting that anti-CD38−targeted therapy not only safeguards the cell-specific cytotoxic CD8+ T cells but also promotes antibody-specific immunity. These results suggested that targeting CD38 may offer an alternative treatment approach for refractory or relapsed patients with CTCL if they specifically express CD38 on their neoplastic cells (Figure 1c).
provide a promising result for targeting CD38 in aggressive and treatment-refractory CTCL. A deep dive into the flow cytometry data show that the tumor cells from patients with SS express only an intermediate level of CD38, which is lower than the expression level on benign CD4+ T cells. In addition, looking into the unsupervised clustering of single-cell sequencing data from skin cell subsets, the CD38-positive cells mainly belong to lymphocytes, myeloid lineages (macrophage and DCs), and a small proportion of fibrocytes and keratinocytes. This implies a potential off-target effect on benign cells. Hence, checking CD38 expression on neoplastic cells and evaluating the impact on peripheral cells before therapeutic targeting of CD38 is of pivotal importance.
For the immunochemistry study, in total, 56 patients with different CTCL subtypes were enrolled. The result indicated a subpopulation of aggressive CTCLs with abnormal CD38 overexpression in the skin. Moreover, the presence of CD38 in skin lesions inversely correlated with overall survival. To deeper understand the impact of CD38 expression in the prognosis of patients with CTCL as well as the efficacy of target therapy with anti-CD38 mAbs, a comprehensive investigation with a larger study cohort will be interesting and worth investment.
In conclusion, the evidences provided in this study shed the light on a potential personalized therapy for a subpopulation of an aggressive form of CTCL, which overexpress CD38.
Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.
The treatment of advanced-stage cutaneous T-cell lymphomas (CTCLs) remains challenging. CD38 is a multifunctional ectoenzyme with nicotinamide adenine dinucleotide–depleting and intracellular signaling activities uniformly expressed by myeloma cells and other hematopoietic cells. In T cells, it functions as an adhesion molecule to CD31 expressed by endothelial cells, and its ligation induces the production of cytokines (Ausiello et al., 1995).
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