三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和抗HER2靶向治疗无效，对化疗容易耐药，对免疫治疗也容易产生免疫逃逸和耐药。除了免疫治疗药物，疫苗也可用于治疗癌症，无论免疫治疗药物还是疫苗，大多通过激活后天免疫系统的T淋巴细胞，针对癌细胞表面的特定蛋白质抗原而发挥作用，也就是一把钥匙开一把锁。可是，癌细胞与病毒一样，都可通过变异改变蛋白质抗原，如同改变锁孔，从而逃避T淋巴细胞的追杀。
2022年5月25日，全球自然科学三大旗舰期刊之首、英国《自然》正刊在线发表美国哈佛大学、达纳法伯癌症研究院、布莱根医院和波士顿妇女医院、埃默里大学、日本和歌山医科大学的研究报告，设计了一种新的疫苗，可同时激活T淋巴细胞和自然杀伤细胞，对癌细胞进行攻击。自然杀伤细胞又称天然杀手细胞或大颗粒淋巴细胞，属于先天免疫系统，可通杀各种病原体和癌细胞。
该研究设计的新疫苗可针对多种人类癌症由于DNA损伤而表达的应激蛋白MICA和MICB，能够激活T淋巴细胞和自然杀伤细胞的NKG2D受体，加速免疫系统消灭肿瘤。可是，道高一寸，魔高一尺，癌细胞又可通过蛋白质水解作用对MICA和MICB进行分解切割，从而逃避免疫攻击。不过，魔高一尺，道高一丈，该新疫苗可诱导抗体通过抑制癌细胞蛋白质水解作用，增加癌细胞表面MICA和MICB的密度，增强树突状细胞向T淋巴细胞呈递肿瘤抗原，并增强自然杀伤细胞的细胞毒性功能。
值得注意的是，该新疫苗通过自然杀伤细胞和CD4阳性T淋巴细胞的协同作用，对能够抵抗细胞毒性T淋巴细胞的主要组织相容性复合体I类基因缺陷型肿瘤也有效，CD8阳性T淋巴细胞、CD4阳性T细胞、自然杀伤细胞数量分别达对照组的17.9倍、29.3倍、38.9倍，能够抗肿瘤的干扰素γ和肿瘤坏死因子α水平显著提高，PD-1、CTLA-4、Tim-3、Tigit、Lag3等免疫抑制受体表达水平显著降低。
该新疫苗对三阴性乳腺癌4T1、黑色素瘤B16-BL6等高度恶性癌细胞建立的小鼠体内模型也十分有效：手术切除原发高度转移性肿瘤后，接种该新疫苗，可显著抑制癌细胞的生长和转移，而且几乎不影响健康细胞。
因此，该研究结果表明，该新疫苗设计方法可提供保护性免疫治疗作用，甚至可针对常见的免疫逃逸突变肿瘤，为对抗三阴性乳腺癌等难治性人类癌症奠定了基础，故有必要进一步开展人体临床研究进行验证。
Nature. 2022 May 25. Online ahead of print.A vaccine targeting resistant tumours by dual T cell plus NK cell attack.Badrinath S, Dellacherie MO, Li A, Zheng S, Zhang X, Sobral M, Pyrdol JW, Smith KL, Lu Y, Haag S, Ijaz H, Connor-Stroud F, Kaisho T, Dranoff G, Yuan GC, Mooney DJ, Wucherpfennig KW.Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Harvard University, Cambridge, MA, USA; Harvard University, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA; Emory University, Atlanta, GA, USA; Wakayama Medical University, Wakayama, Japan.Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.DOI: 10.1038/s41586-022-04772-4
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