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CD38 in Adenosinergic Pathways and Metabolic Re-programming in Human Multiple Myeloma Cells: In-tandem Insights From Basic Science to Therapy

机译：CD38在人多发性骨髓瘤细胞中的腺苷能途径和代谢重编程：从基础科学到治疗学的串联见解

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Tumor microenvironments are rich in extracellular nucleotides that can be metabolized by ectoenzymes to produce adenosine, a nucleoside involved in controlling immune responses. Multiple myeloma, a plasma cell malignancy developed within a bone marrow niche, exploits adenosinergic pathways to customize the immune homeostasis of the tumor. CD38, a multifunctional protein that acts as both receptor and ectoenzyme, is overexpressed at all stages of myeloma. At neutral and acidic pH, CD38 catalyzes the extracellular conversion of NAD+ to regulators of calcium signaling. The initial disassembly of NAD+ is also followed by adenosinergic activity, if CD38 is operating in the presence of CD203a and CD73 nucleotidases. cAMP extruded from tumor cells provides another substrate for metabolizing nucleotidases to signaling adenosine. These pathways flank or bypass the canonical adenosinergic pathway subjected to the conversion of ATP by CD39. All of the adenosinergic networks can be hijacked by the tumor, thus controlling the homeostatic reprogramming of the myeloma in the bone marrow. In this context, adenosine assumes the role of a local hormone: cell metabolism is adjusted via low- or high-affinity purinergic receptors expressed by immune and bone cells as well as by tumor cells. The result is immunosuppression, which contributes to the failure of immune surveillance in cancer. A similar metabolic strategy silences immune effectors during the progression of indolent gammopathies to symptomatic overt multiple myeloma disease. Plasma from myeloma aspirates contains elevated levels of adenosine resulting from interactions between myeloma and other cells lining the niche and adenosine concentrations are known to increase as the disease progresses. This is statistically reflected in the International Staging System for multiple myeloma. Along with the ability to deplete CD38+ malignant plasma cell populations which has led to their widespread therapeutic use, anti-CD38 antibodies are involved in the polarization and release of microvesicles characterized by the expression of multiple adenosine-producing molecules. These adenosinergic pathways provide new immune checkpoints for improving immunotherapy protocols by helping to restore the depressed immune response.
机译：肿瘤微环境富含细胞外核苷酸，可被胞外酶代谢产生腺苷，腺苷是一种参与控制免疫反应的核苷。多发性骨髓瘤是骨髓小生境中发展起来的浆细胞恶性肿瘤，它利用腺苷能途径来定制肿瘤的免疫稳态。 CD38是一种同时充当受体和外切酶的多功能蛋白质，在骨髓瘤的所有阶段均过表达。在中性和酸性pH值下，CD38催化NAD + 向钙信号调节剂的细胞外转化。如果CD38在CD203a和CD73核苷酸酶的存在下运行，则NAD + 的最初拆卸也伴随着腺苷能活性。从肿瘤细胞中挤出的cAMP为将核苷酸酶代谢为信号腺苷提供了另一种底物。这些途径侧翼或绕过经过CD39进行ATP转换的典型腺苷能途径。肿瘤可以劫持所有的腺苷能网络，从而控制骨髓中骨髓瘤的稳态重编程。在这种情况下，腺苷承担着局部激素的作用：细胞的代谢是通过免疫细胞，骨细胞以及肿瘤细胞表达的低或高亲和力嘌呤受体调节的。结果是免疫抑制，导致癌症免疫监测失败。类似的代谢策略在惰性变态反应发展为有症状的多发性骨髓瘤疾病的过程中使免疫效应沉默。骨髓瘤抽出物的血浆中含有升高水平的腺苷，这是由于骨髓瘤与其他位于壁iche中的细胞之间的相互作用所致，已知腺苷浓度随疾病的进展而增加。统计上反映在国际多发性骨髓瘤分期系统中。除耗尽CD38 + 恶性浆细胞群的能力已导致其广泛的治疗用途外，抗CD38抗体还参与了以表达多种腺苷的表达为特征的微泡的极化和释放。分子。这些腺苷能途径通过帮助恢复低下的免疫应答，为改善免疫疗法方案提供了新的免疫检查点。

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