Nahar Saifun, Huang Yue, Nagy Bethany A, Zebala John A, Maeda Dean Y, Rudloff Udo, Oppenheim Joost J, Yang De
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Cancers (Basel). 2023 Apr 19;15(8):2366. doi: 10.3390/cancers15082366.
Triple-negative breast carcinoma (TNBC) is one of the most aggressive types of solid-organ cancers. While immune checkpoint blockade (ICB) therapy has significantly improved outcomes in certain types of solid-organ cancers, patients with immunologically cold TNBC are afforded only a modest gain in survival by the addition of ICB to systemic chemotherapy. Thus, it is urgently needed to develop novel effective therapeutic approaches for TNBC. Utilizing the 4T1 murine model of TNBC, we developed a novel combination immunotherapeutic regimen consisting of intratumoral delivery of high-mobility group nucleosome binding protein 1 (HMGN1), TLR2/6 ligand fibroblast-stimulating lipopeptide (FSL-1), TLR7/8 agonist (R848/resiquimod), and CTLA-4 blockade. We also investigated the effect of adding SX682, a small-molecule inhibitor of CXCR1/2 known to reduce MDSC trafficking to tumor microenvironment, to our therapeutic approach. 4T1-bearing mice responded with significant tumor regression and tumor elimination to our therapeutic combination regimen. Mice with complete tumor regressions did not recur and became long-term survivors. Treatment with HMGN1, FSL-1, R848, and anti-CTLA4 antibody increased the number of infiltrating CD4+ and CD8+ effector/memory T cells in both tumors and draining lymph nodes and triggered the generation of 4T1-specific cytotoxic T lymphocytes (CTLs) in the draining lymph nodes. Thus, we developed a potentially curative immunotherapeutic regimen consisting of HMGN1, FSL-1, R848, plus a checkpoint inhibitor for TNBC, which does not rely on the administration of chemotherapy, radiation, or exogenous tumor-associated antigen(s).
三阴性乳腺癌（TNBC）是实体器官癌中侵袭性最强的类型之一。虽然免疫检查点阻断（ICB）疗法显著改善了某些类型实体器官癌的治疗效果，但免疫冷型TNBC患者在全身化疗基础上加用ICB后，生存期仅略有延长。因此，迫切需要为TNBC开发新的有效治疗方法。利用TNBC的4T1小鼠模型，我们开发了一种新型联合免疫治疗方案，包括瘤内递送高迁移率族核小体结合蛋白1（HMGN1）、TLR2/6配体成纤维细胞刺激脂肽（FSL-1）、TLR7/8激动剂（R848/瑞喹莫德）以及CTLA-4阻断。我们还研究了在治疗方案中加入SX682（一种已知可减少骨髓来源的抑制性细胞（MDSC）向肿瘤微环境迁移的CXCR1/2小分子抑制剂）的效果。携带4T1肿瘤的小鼠对我们的联合治疗方案产生了显著的肿瘤消退和肿瘤清除反应。肿瘤完全消退的小鼠没有复发，并成为长期存活者。用HMGN1、FSL-1、R848和抗CTLA4抗体治疗可增加肿瘤和引流淋巴结中浸润的CD4+和CD8+效应/记忆T细胞数量，并在引流淋巴结中触发4T1特异性细胞毒性T淋巴细胞（CTL）的产生。因此，我们开发了一种潜在的治愈性免疫治疗方案，由HMGN1、FSL-1、R848加上一种用于TNBC的检查点抑制剂组成，该方案不依赖于化疗、放疗或外源性肿瘤相关抗原的给药。
