Dhodapkar Kavita M, Gettinger Scott N, Das Rituparna, Zebroski Henry, Dhodapkar Madhav V
Department of Pediatrics; Yale University; New Haven, CT USA ; Yale Cancer Center; Yale University; New Haven, CT USA.
Oncoimmunology. 2013 Jul 1;2(7):e25205. doi: 10.4161/onci.25205. Epub 2013 Jun 10.
Immunotherapeutic strategies including the blockade of programmed death 1 (PD-1) receptors hold promise for the treatment of various cancers including non-small cell lung carcinoma (NSCLC). Preclinical data suggest that pre-existing tumor immunity is important for disease regression upon checkpoint blockade-based therapies. However, the nature of antigen-specific T-cell responses that correlate with the clinical response to immunotherapy in NSCLC patients is not known. The embryonic stem cell gene SRY (sex determining region Y)-box 2 () has recently emerged as a major oncogenic driver in NSCLC. Here, we show that nearly 50% of a cohort of NSCLC patients mounted both CD4 and CD8 T-cell responses against SOX2, which could be readily detected among peripheral blood mononuclear cells. T-cell responses against SOX2 were associated with NSCLC regression upon immunotherapy with anti-PD-1 monoclonal antibodies, whereas none of the patients lacking SOX2-specific T cells experienced disease regression following immune checkpoint blockade. Conversely, cellular and humoral responses against viral antigens or another tumor-associated antigen (NY-ESO-1) failed to correlate with the clinical response of NSCLC patients to immunotherapy. Of note, the administration of PD-1-blocking antibodies was associated with intramolecular epitope spread as well as with the amplification of SOX2-specific immune responses in vivo. These findings identify SOX2 as an important tumor-associated antigen in NSCLC and link the presence of SOX2-specific T cells with the clinical response of lung cancer patients to immunotherapy.
包括阻断程序性死亡1（PD-1）受体在内的免疫治疗策略有望用于治疗包括非小细胞肺癌（NSCLC）在内的多种癌症。临床前数据表明，预先存在的肿瘤免疫对于基于检查点阻断的疗法实现疾病消退很重要。然而，与NSCLC患者免疫治疗临床反应相关的抗原特异性T细胞反应的本质尚不清楚。胚胎干细胞基因SRY（性别决定区Y）-盒2（）最近已成为NSCLC中的主要致癌驱动因素。在此，我们表明，在一组NSCLC患者中，近50%产生了针对SOX2的CD4和CD8 T细胞反应，在外周血单个核细胞中很容易检测到。针对SOX2的T细胞反应与抗PD-1单克隆抗体免疫治疗后的NSCLC消退相关，而缺乏SOX2特异性T细胞的患者在免疫检查点阻断后均未出现疾病消退。相反，针对病毒抗原或另一种肿瘤相关抗原（NY-ESO-1）的细胞和体液反应与NSCLC患者的免疫治疗临床反应无关。值得注意的是，给予PD-1阻断抗体与分子内表位扩展以及体内SOX2特异性免疫反应的放大有关。这些发现确定SOX2是NSCLC中一种重要的肿瘤相关抗原，并将SOX2特异性T细胞的存在与肺癌患者免疫治疗的临床反应联系起来。
