Ruffin Ayana T, Casey Allison N, Kunning Sheryl R, MacFawn Ian P, Liu Zhentao, Arora Charu, Rohatgi Anjali, Kemp Felicia, Lampenfeld Caleb, Somasundaram Ashwin, Rappocciolo Giovanna, Kirkwood John M, Duvvuri Umamaheswar, Seethala Raja, Bao Riyue, Huang Yufei, Cillo Anthony R, Ferris Robert L, Bruno Tullia C
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh, PA 15213, USA.
Sci Transl Med. 2025 Feb 19;17(786):eadh1315. doi: 10.1126/scitranslmed.adh1315.
Many patients with recurrent and metastatic cancer fail to produce a durable response to immunotherapy, highlighting the need for additional therapeutic targets to improve the immune landscape in tumors. Recent studies have highlighted the importance of B cells in the antitumor response, with memory B cells (MBCs) being prognostic in a variety of solid tumors. MBCs are a heterogenous B cell subset and can be generated through both germinal center reactions and extrafollicular (EF) responses. EF-derived MBCs have been recently linked to poor prognosis and treatment resistance in solid tumors and thus may represent candidate biomarkers or immunotherapy targets. EF-derived MBCs, termed "double-negative" (DN) MBCs may be further classified on the basis of surface expression of CD11c and CD21 into DN1, DN2, and DN3 MBCs. CD11cCD21 DN1 MBCs and CD11cCD21 DN2 MBCs have been well studied across inflammatory diseases; however, the biology and clinical relevance of CD11cCD21 DN3 MBCs remain unknown. Here, we report an accumulation of DN3 MBCs in the blood and tumors of patients with head and neck squamous cell carcinoma (HNSCC) and an increase in DN3 MBCs in locally advanced HNSCC tumors. Circulating and intratumoral DN3 MBCs were hyporesponsive to antigen stimulation, had low antibody production, and failed to differentiate into antibody-secreting cells. Moreover, DN3 MBCs accumulated selectively outside of tertiary lymphoid structures. Last, circulating DN3 MBCs correlated with poor therapeutic response, advanced disease, and worse outcomes in patients with HNSCC and melanoma, supporting further assessment of EF-derived MBCs as potential biomarkers and therapeutic targets.
许多复发和转移性癌症患者对免疫疗法无法产生持久反应，这凸显了需要额外的治疗靶点来改善肿瘤中的免疫格局。最近的研究强调了B细胞在抗肿瘤反应中的重要性，记忆B细胞（MBC）在多种实体瘤中具有预后价值。MBC是一个异质性B细胞亚群，可通过生发中心反应和滤泡外（EF）反应产生。最近，源自EF的MBC与实体瘤的不良预后和治疗耐药性有关，因此可能代表候选生物标志物或免疫治疗靶点。源自EF的MBC，称为“双阴性”（DN）MBC，可根据CD11c和CD21的表面表达进一步分为DN1、DN2和DN3 MBC。CD11cCD21 DN1 MBC和CD11cCD21 DN2 MBC在各种炎症性疾病中已得到充分研究；然而，CD11cCD21 DN3 MBC的生物学特性和临床相关性仍然未知。在这里，我们报告了头颈部鳞状细胞癌（HNSCC）患者血液和肿瘤中DN3 MBC的积累，以及局部晚期HNSCC肿瘤中DN3 MBC的增加。循环和肿瘤内的DN3 MBC对抗原刺激反应低下，抗体产生量低，并且无法分化为抗体分泌细胞。此外，DN3 MBC选择性地在三级淋巴结构之外积累。最后，循环DN3 MBC与HNSCC和黑色素瘤患者的治疗反应差、疾病进展和预后不良相关，支持进一步评估源自EF的MBC作为潜在生物标志物和治疗靶点。
