Kozbor Danuta, Winkler Marta, Malhotra Nemi, Mistarz Anna, Wang Sophie, Hutson Alan, Gambotto Andrea, Abrams Scott, Singh Prashant, Liu Song, Odunsi Kunle, Wang Jianmin
Roswell Park Cancer Institute.
Roswell Park Comprehensive Cancer Center.
Res Sq. 2024 Sep 17:rs.3.rs-4940287. doi: 10.21203/rs.3.rs-4940287/v1.
The treatment-induced activation level within the perivascular tumor microenvironment (TME) that supports T-cell trafficking and optimal T-cell differentiation is unknown. We investigated the mechanisms by which inflammatory responses generated by tumor-specific T cells delivered to ovarian tumor-bearing mice alone or after oncolytic vaccinia virus-driven immunogenic cancer cell death affect antitumor efficacy. Analyses of the perivascular TME by spatially resolved omics technologies revealed reduced immunosuppression and increased tumoricidal T-cell trafficking and function after moderate inflammatory responses driven by a CXCR4 antagonist-armed oncolytic virus. Neither weak nor high inflammation created a permissive TME for T-cell trafficking. Notably, treatment-mediated differences in T-cell effector programs acquired within the perivascular TME contrasted with comparable antigenic priming in the tumor-draining lymph nodes regardless of the activation mode of antigen-presenting cells. These findings provide new insights into combinatorial treatment strategies that enable tumor-specific T cells to overcome multiple barriers for enhanced trafficking and control of tumor growth.
支持T细胞运输和最佳T细胞分化的血管周围肿瘤微环境（TME）中治疗诱导的激活水平尚不清楚。我们研究了单独或在溶瘤痘苗病毒驱动的免疫原性癌细胞死亡后递送至荷卵巢肿瘤小鼠的肿瘤特异性T细胞产生的炎症反应影响抗肿瘤疗效的机制。通过空间分辨组学技术对血管周围TME进行分析发现，在携带CXCR4拮抗剂的溶瘤病毒驱动的适度炎症反应后，免疫抑制作用降低，杀肿瘤T细胞运输和功能增强。轻度或高度炎症均未为T细胞运输创造有利的TME。值得注意的是，无论抗原呈递细胞的激活模式如何，血管周围TME内获得的治疗介导的T细胞效应程序差异与肿瘤引流淋巴结中类似的抗原启动形成对比。这些发现为联合治疗策略提供了新的见解，该策略使肿瘤特异性T细胞能够克服多个障碍，以增强运输并控制肿瘤生长。
