Mouri Atsuto, Kaira Kyoichi, Yamaguchi Ou, Shiono Ayako, Miura Yu, Hashimoto Kosuke, Yamasaki Satoshi, Nishihara Fuyumi, Imai Hisao, Kobayashi Kunihiko, Kagamu Hiroshi
Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center,, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
Department of Clinical Cancer Genomics, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
Cancer Immunol Immunother. 2025 Jul 12;74(8):265. doi: 10.1007/s00262-025-04113-0.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) control lung cancer in patients with EGFR mutations, but resistance develops over time. Patients with high levels of genetic mutations rapidly acquire EGFR-TKI resistance. T cell immunity recognizes gene mutation products as neoantigens that effectively suppress mutation levels by eliminating clones with more mutations; this process is known as cancer immune editing. Therefore, EGFR-TKI-resistant clones may be less likely to form in cases with active antitumor T cell immune responses. However, the relationship between EGFR-TKI resistance and antitumor T cell response in patients with EGFR mutation remains unclear. To determine the relationship between the duration of EGFR-TKI resistance acquisition and antitumor T cell immunity, and the effect of EGFR-TKIs on T cell immunity.
This prospective observational study enrolled 43 patients who received osimertinib. Blood samples were collected prior to and following 4 weeks of EGFR-TKI administration.
The median PFS and OS for the 37 patients were 24.8 and 32.9 months, respectively. Patients with higher CXCR3CCR4CCR6CD4 T cell levels exhibited significantly enhanced PFS (p = 0.002) and OS (p = 0.0006). Other T cell subsets (Th1, Th2, Th17, and CD8) exhibited no significant correlation with PFS. The percentage of CXCR3CCR4CCR6CD4 T cells was significantly reduced with tumor volume reduction (p < 0.0001).
T cell immunity affects the time required to acquire resistance after EGFR-TKI treatment. Pretreatment CXCR3CCR4CCR6CD4 T cell cluster was significantly associated with PFS after osimertinib treatment, likely predicting osimertinib efficacy. Antitumor T cell immunity may be crucial for preventing the acquisition of EGFR-TKI resistance.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）可控制表皮生长因子受体（EGFR）突变患者的肺癌，但随着时间推移会产生耐药性。基因突变水平高的患者会迅速获得EGFR-TKI耐药性。T细胞免疫将基因突变产物识别为新抗原，通过消除具有更多突变的克隆来有效抑制突变水平；这一过程被称为癌症免疫编辑。因此，在具有活跃抗肿瘤T细胞免疫反应的情况下，EGFR-TKI耐药克隆形成的可能性可能较小。然而，EGFR突变患者中EGFR-TKI耐药性与抗肿瘤T细胞反应之间的关系仍不清楚。为了确定EGFR-TKI耐药获得时间与抗肿瘤T细胞免疫之间的关系，以及EGFR-TKIs对T细胞免疫的影响。
这项前瞻性观察性研究纳入了43例接受奥希替尼治疗的患者。在EGFR-TKI给药前和给药4周后采集血样。
37例患者的中位无进展生存期（PFS）和总生存期（OS）分别为24.8个月和32.9个月。CXCR3⁺CCR4⁺CCR6⁺CD4⁺T细胞水平较高的患者PFS（p = 0.002）和OS（p = 0.0006）显著延长。其他T细胞亚群（Th1、Th2、Th17和CD8）与PFS无显著相关性。随着肿瘤体积减小，CXCR3⁺CCR4⁺CCR6⁺CD4⁺T细胞百分比显著降低（p < 0.0001）。
T细胞免疫影响EGFR-TKI治疗后获得耐药性所需的时间。治疗前CXCR3⁺CCR4⁺CCR6⁺CD4⁺T细胞簇与奥希替尼治疗后的PFS显著相关，可能预测奥希替尼疗效。抗肿瘤T细胞免疫对于预防EGFR-TKI耐药性的获得可能至关重要。
