Ramamoorthi Ganesan, Lee Marie Catherine, Farrell Carly M, Snyder Colin, Garg Saurabh K, Aldrich Amy L, Lok Vincent, Dominguez-Viqueira William, Olson-Mcpeek Sy K, Rosa Marilin, Gautam Namrata, Pilon-Thomas Shari, Cen Ling, Kodumudi Krithika N, Wiener Doris, Oskarsson Thordur, Gomes Ana P, Gatenby Robert A, Czerniecki Brian J
Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida.
Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida.
Cancer Immunol Res. 2025 May 2;13(5):729-748. doi: 10.1158/2326-6066.CIR-24-0630.
Detection of disseminated cancer cells (DCC) in the bone marrow (BM) of patients with breast cancer is a critical predictor of late recurrence and distant metastasis. Conventional therapies often fail to completely eradicate DCCs in patients. In this study, we demonstrate that intratumoral priming of antitumor CD4+ T helper 1 (Th1) cells was able to eliminate the DCC burden in distant organs and prevent overt metastasis, independent of CD8+ T cells. Intratumoral priming of tumor antigen-specific CD4+ Th1 cells enhanced their migration to the BM and distant metastatic site to selectively target DCC burden. The majority of these intratumorally activated CD4+ T cells were CD4+PD1- T cells, supporting their nonexhaustion stage. Phenotypic characterization revealed enhanced infiltration of memory CD4+ T cells and effector CD4+ T cells in the primary tumor, tumor-draining lymph node, and DCC-driven metastasis site. A robust migration of CD4+CCR7+CXCR3+ Th1 cells and CD4+CCR7-CXCR3+ Th1 cells into distant organs further revealed their potential role in eradicating DCC-driven metastasis. The intratumoral priming of antitumor CD4+ Th1 cells failed to eradicate DCC-driven metastasis in CD4- or IFN-γ knockout mice. Moreover, antitumor CD4+ Th1 cells, by increasing IFN-γ production, inhibited various molecular aspects and increased classical and nonclassical MHC molecule expression in DCCs. This reduced stemness and self-renewal while increasing immune recognition in DCCs of patients with breast cancer. These results unveil an immune basis for antitumor CD4+ Th1 cells that modulate DCC tumorigenesis to prevent recurrence and metastasis in patients.
检测乳腺癌患者骨髓（BM）中的播散癌细胞（DCC）是晚期复发和远处转移的关键预测指标。传统疗法往往无法完全根除患者体内的DCC。在本研究中，我们证明肿瘤内启动抗肿瘤CD4 +辅助性T细胞1（Th1）能够消除远处器官中的DCC负担并预防明显转移，这一过程独立于CD8 + T细胞。肿瘤内启动肿瘤抗原特异性CD4 + Th1细胞可增强其向骨髓和远处转移部位的迁移，以选择性地靶向DCC负担。这些肿瘤内活化的CD4 + T细胞大多数是CD4 + PD1- T细胞，表明它们处于未耗竭阶段。表型特征显示，原发性肿瘤、肿瘤引流淋巴结和DCC驱动的转移部位中记忆性CD4 + T细胞和效应性CD4 + T细胞的浸润增强。CD4 + CCR7 + CXCR3 + Th1细胞和CD4 + CCR7-CXCR3 + Th1细胞向远处器官的强劲迁移进一步揭示了它们在根除DCC驱动的转移中的潜在作用。在CD4或IFN-γ基因敲除小鼠中，肿瘤内启动抗肿瘤CD4 + Th1细胞未能根除DCC驱动的转移。此外，抗肿瘤CD4 + Th1细胞通过增加IFN-γ的产生，抑制了DCC的各种分子特征，并增加了经典和非经典MHC分子的表达。这降低了DCC的干性和自我更新能力，同时增强了乳腺癌患者DCC中的免疫识别。这些结果揭示了抗肿瘤CD4 + Th1细胞调节DCC肿瘤发生以预防患者复发和转移的免疫基础。
