Meng Qingda, Valentini Davide, Rao Martin, Maeurer Markus
Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.
Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Stockholm, Sweden.
Front Oncol. 2018 Sep 19;8:384. doi: 10.3389/fonc.2018.00384. eCollection 2018.
KRAS is a driver mutation for malignant transformation. It is found in 30% of all cancers and in 90% of pancreatic cancers. The identification of small molecules selectively inhibiting KRAS mutants has been challenging, yet mutant KRAS has recently been shown to be targeted by tumor-infiltrating lymphocyte (TIL)-derived T cells that confer tumor regression upon adoptive transfer. Furthermore, a human IgG1 monoclonal antibody interfering with mutant KRAS function inside the cell has been described to inhibit growth of KRAS-mutant xenografts in tumor-bearing mice. B cells have been described to infiltrate pancreatic cancer and may be associated with tertiary lymphoid structures associated with good prognosis, or, in contrast, promote tumor growth. However, their function, nor their antigen-specificity has been clearly defined. We discuss here the presence of tumor-infiltrating B cells (TIB) in patients with pancreatic cancer that produce KRAS-mutant specific IgG, underlining that intratumoral T and B cells may exclusively target mutant KRAS. KRAS-specific IgG may, therefore, serve as a readout of the activation of both arms of the anti-tumor adaptive immune armament although some B-cell populations may promote tumor progression.
KRAS是恶性转化的驱动突变。它在所有癌症的30%以及胰腺癌的90%中被发现。鉴定选择性抑制KRAS突变体的小分子具有挑战性，然而最近已表明突变型KRAS可被肿瘤浸润淋巴细胞（TIL）来源的T细胞靶向，这些T细胞在过继转移后可使肿瘤消退。此外，一种干扰细胞内突变型KRAS功能的人IgG1单克隆抗体已被描述可抑制荷瘤小鼠体内KRAS突变体异种移植物的生长。B细胞已被描述可浸润胰腺癌，可能与预后良好相关的三级淋巴结构有关，或者相反，促进肿瘤生长。然而，它们的功能及其抗原特异性尚未明确界定。我们在此讨论胰腺癌患者中产生KRAS突变体特异性IgG的肿瘤浸润B细胞（TIB）的存在，强调肿瘤内的T细胞和B细胞可能仅靶向突变型KRAS。因此，KRAS特异性IgG可作为抗肿瘤适应性免疫武器库双臂激活的一个指标，尽管一些B细胞群体可能促进肿瘤进展。
