Pelzl Richard, Benintende Giulia, Gsottberger Franziska, Scholz Julia Katharina, Ruebner Matthias, Yao Hao, Wendland Kerstin, Rejeski Kai, Altmann Heidi, Petkovic Srdjan, Mellenthin Lisa, Kübel Sabrina, Schmiedeberg Moritz, Klein Paulina, Petrera Agnese, Baur Rebecca, Eckstein Sophie, Hoepffner-Grundy Sandra, Röllig Christoph, Subklewe Marion, Huebner Hanna, Schett Georg, Mackensen Andreas, Laurenti Luca, Graw Frederik, Völkl Simon, Nganou-Makamdop Krystelle, Müller Fabian
University Hospital of Erlangen, Erlangen, Germany.
Universtiy Hosptial of Erlangen, Erlangen, Germany.
Blood. 2025 May 13. doi: 10.1182/blood.2024027877.
Immunotherapy has become standard of care in the treatment of diffuse large B-cell lymphoma (DLBCL). Changes in immunophenotypes observed at first diagnosis predict therapy outcome but little is known about the resolution of these alterations in remission. Comprehensive characterization of immune changes from fresh, peripheral whole blood revealed a functionally relevant increase of myeloid-derived suppressor cells, reduced naïve T-cells, and an increase of activated and terminally differentiated T-cells before treatment which aggravated after therapy. Suggesting causal relation, injection of lymphoma in mice induced similar changes in the murine T cells. Distinct immune imprints were found in breast cancer and AML survivors. Identified alterations persisted beyond five years of ongoing complete remission and in DLBCL correlated with increased pro-inflammatory markers such as IL-6, B2M, or sCD14. The chronic inflammation was associated with functionally blunted T-cell immunity against SARS-CoV-2-specific peptides and reduced responses correlated with reduced Tn-cells. Persisting inflammation was confirmed by deep sequencing and by cytokine profiles, together pointing towards a compensatory activation of innate immunity. The persisting, lymphoma-induced immune alterations in remission may explain long-term complications, have implications for vaccine strategies, and are likely relevant for immunotherapies.
免疫疗法已成为弥漫性大B细胞淋巴瘤（DLBCL）治疗的标准疗法。首次诊断时观察到的免疫表型变化可预测治疗结果，但对于缓解期这些改变的消退情况知之甚少。对新鲜外周全血中免疫变化的全面表征显示，治疗前髓系来源的抑制细胞功能相关增加、幼稚T细胞减少以及活化和终末分化T细胞增加，治疗后这些情况进一步加重。提示存在因果关系的是，给小鼠注射淋巴瘤会诱导小鼠T细胞发生类似变化。在乳腺癌和急性髓系白血病（AML）幸存者中发现了不同的免疫印记。所确定的改变在持续完全缓解超过五年后仍然存在，并且在DLBCL中与促炎标志物如白细胞介素-6（IL-6）、β2微球蛋白（B2M）或可溶性CD14增加相关。慢性炎症与针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）特异性肽的T细胞免疫功能减弱相关，反应降低与Tn细胞减少相关。通过深度测序和细胞因子谱证实了持续炎症的存在，共同指向先天免疫的代偿性激活。缓解期持续存在的、淋巴瘤诱导的免疫改变可能解释长期并发症，对疫苗策略有影响，并且可能与免疫疗法相关。
