Tumor cell heterogeneity drives spatial organization of the intratumoral immune response in squamous cell skin carcinoma.
Tumor cell heterogeneity drives spatial organization of the intratumoral immune response in squamous cell skin carcinoma.
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肿瘤细胞异质性驱动鳞状细胞皮肤癌瘤内免疫反应的空间组织。
DOI：
10.1101/2023.04.25.538140
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Reeves,Melissa
中科院分区：
文献类型：
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作者：
Tanaka,Miho;Lum,Lotus;Hu,Kenneth;Ledezma-Soto,Cecilia;Samad,Bushra;Superville,Daphne;Ng,Kenneth;Adams,Zoe;Kersten,Kelly;Fong,Lawrence;Combes,AlexisJ;Krummel,Matthew;Reeves,Melissa
肿瘤内异质性（ITH）-定义为肿瘤内的遗传和细胞多样性-与免疫治疗失败和抗肿瘤免疫应答低下有关。这种关联的潜在机制尚不清楚。为了解决这个问题，我们模拟了由促炎性（“热”）和免疫抑制性（“冷”）肿瘤群体组成的异质性肿瘤，分别用YFP和RFP标签标记以实现精确的空间跟踪。所得混合群体肿瘤表现出由YFP+（热）细胞、RFP+（冷）细胞或混合物组成的不同区域。我们发现，与冷肿瘤细胞（RFP+）占据的区域相比，热肿瘤细胞（YFP+）占据的肿瘤区域具有更多的总T细胞和更高频率的Th 1细胞和IFNγ+ CD 8 T细胞，而免疫抑制性巨噬细胞显示相反的空间模式。我们鉴定了趋化因子CX 3CL 1，其由我们的冷肿瘤以较高水平产生，作为肿瘤内巨噬细胞积聚的介体，特别是免疫抑制性CD 206 Hi巨噬细胞。此外，我们在逐区域的基础上检查了异质性肿瘤对PD-1阻断剂和CD 40激动剂的治疗组合的反应。虽然该组合成功地增加了“冷”肿瘤区域中的Th 1丰度，但它未能使整体T细胞活性达到与“热”区域相同的水平。因此，“冷”细胞的存在最终导致诱导肿瘤排斥的治疗失败。总的来说，我们的研究结果表明，异质性肿瘤细胞的组织对指导肿瘤浸润免疫细胞的空间组织和功能以及对免疫治疗的反应具有深远的影响。
Intratumoral heterogeneity (ITH)—defined as genetic and cellular diversity within a tumor—is linked to failure of immunotherapy and an inferior anti-tumor immune response. The underlying mechanism of this association is unknown. To address this question, we modeled heterogeneous tumors comprised of a pro-inflammatory (“hot”) and an immunosuppressive (“cold”) tumor population, labeled with YFP and RFP tags respectively to enable precise spatial tracking. The resulting mixed-population tumors exhibited distinct regions comprised of YFP+ (hot) cells, RFP+ (cold) cells, or a mixture. We found that tumor regions occupied by hot tumor cells (YFP+) harbored more total T cells and a higher frequency of Th1 cells and IFNγ+ CD8 T cells compared to regions occupied by cold tumor cells (RFP+), whereas immunosuppressive macrophages showed the opposite spatial pattern. We identified the chemokine CX3CL1, produced at higher levels by our cold tumors, as a mediator of intratumoral macrophage accumulation, particularly immunosuppressive CD206Hi macrophages. Furthermore, we examined the response of heterogeneous tumors to a therapeutic combination of PD-1 blockade and CD40 agonist on a region-by-region basis. While the combination successfully increases Th1 abundance in “cold” tumor regions, it fails to bring overall T cell activity to the same level as seen in “hot” regions. The presence of the “cold” cells thus ultimately leads to a failure of the therapy to induce tumor rejection. Collectively, our results demonstrate that the organization of heterogeneous tumor cells has a profound impact on directing the spatial organization and function of tumor-infiltrating immune cells as well as on responses to immunotherapy.