Differential responses to immune checkpoint inhibitor dictated by pre-existing differential immune profiles in squamous cell carcinomas caused by same initial oncogenic drivers.
Differential responses to immune checkpoint inhibitor dictated by pre-existing differential immune profiles in squamous cell carcinomas caused by same initial oncogenic drivers.
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DOI：
10.1186/s13046-022-02337-x
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发表时间：
2022-04-02
期刊：
影响因子：
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通讯作者：
Wang JH
中科院分区：
文献类型：
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作者：
Chen SMY;Popolizio V;Woolaver RA;Ge H;Krinsky AL;John J;Danis E;Ke Y;Kramer Y;Bian L;Nicklawsky AG;Gao D;Liu S;Chen Z;Wang XJ;Wang JH
虽然批准了头颈部鳞状细胞癌（HNSCC）的免疫检查点抑制剂（ICI），但反应率仍然相对较低。 ICI无反应性与灵敏度的机制尚未完全理解。
为了更好地描述对ICI处理的差异反应，我们采用了小鼠SCC模型，称为KPPA肿瘤，这些模型是由删除p53和过度激活PIK3CA引起的，这是人类HNSCC中两个最常见的基因。我们将两条KPPA肿瘤系（TAB2与TCH3）移植到C57BL/6受体中，并使用流式细胞仪检查了免疫肿瘤微环境。此外，我们采用了单细胞RNA测序来确定肿瘤浸润淋巴细胞（TIL）的差异。
我们发现，不同的KPPA肿瘤表现出异质的免疫特征预先存在的治疗，这决定了它们对抗PD-L1的敏感性或无反应性。无反应的TAB2肿瘤高度富含与功能性肿瘤相关的巨噬细胞（TAM），尤其是M2-TAM。相比之下，敏感的TCH3肿瘤包含更多具有更好效应函数的CD8 TIL。 TAB2肿瘤细胞从需要CSF1和VEGF的骨髓前体中大幅扩展了F4/80+ TAM。一致地，VEGF-C和CSF1的较高组合表达预测，PIK3CAAMP/TP53MUTAT的HNSCC患者的生存率较差。无反应的TAB2肿瘤上调了与侵袭性肿瘤表型相关的不同信号通路。虽然抗PD-L1不影响TAB2肿瘤的TME，但它显着增加了TCH3肿瘤中CD8 TIL的数量。
我们发现了通过建立和采用两种SCC肿瘤系的差异反应，即TAB2与TCH3，这可能是对ICI的差异反应，这两者都具有TP53缺失和PIK3CA过度激活。我们的研究表明，根据癌症的遗传改变了分层的局限性，并表明评估HNSCC肿瘤 - 内膜提示以及TME中的免疫特征可能有助于更好地预测ICI反应。我们的实验模型可以提供一个平台，用于指出HNSCC中免疫抑制性TME的肿瘤内部差异，并测试针对靶向肿瘤特异性或TAM特异性参与者的合并免疫疗法以提高ICI效果。
在线版本包含的补充材料可获得10.1186/s13046-022-02337-X。
While immune checkpoint inhibitors (ICI) were approved for head and neck squamous cell carcinomas (HNSCCs), the response rate remains relatively low. Mechanisms underlying ICI unresponsiveness versus sensitivity are not fully understood. To better delineate differential responses to ICI treatment, we employed mouse SCC models, termed KPPA tumors that were caused by deleting p53 and hyperactivating PIK3CA, two most frequently mutated genes in human HNSCCs. We transplanted two KPPA tumor lines (TAb2 versus TCh3) into C57BL/6 recipients and examined the immune tumor microenvironment using flow cytometry. Furthermore, we employed single-cell RNA sequencing to identify the difference in tumor infiltrating lymphocytes (TILs). We found that different KPPA tumors exhibited heterogeneous immune profiles pre-existing treatment that dictated their sensitivity or unresponsiveness to anti-PD-L1. Unresponsive TAb2 tumors were highly enriched with functional tumor-associated macrophages (TAMs), especially M2-TAMs. In contrast, sensitive TCh3 tumors contained more CD8 TILs with better effector functions. TAb2 tumor cells drastically expanded F4/80+ TAMs from bone marrow precursors, requiring CSF1 and VEGF. Consistently, a higher combined expression of VEGF-C and CSF1 predicts worse survival in PIK3CAAmp/TP53Mutated HNSCC patients. Unresponsive TAb2 tumors upregulated distinct signaling pathways that correlate with aggressive tumor phenotypes. While anti-PD-L1 did not affect the TME of TAb2 tumors, it significantly increased the number of CD8 TILs in TCh3 tumors. We uncovered tumor-intrinsic differences that may underlie the differential responses to ICI by establishing and employing two SCC tumor lines, TAb2 vs. TCh3, both of which harbor TP53 deletion and PIK3CA hyperactivation. Our study indicates the limitation of stratifying cancers according to their genetic alterations and suggests that evaluating HNSCC tumor-intrinsic cues along with immune profiles in the TME may help better predict ICI responses. Our experimental models may provide a platform for pinpointing tumor-intrinsic differences underlying an immunosuppressive TME in HNSCCs and for testing combined immunotherapies targeting either tumor-specific or TAM-specific players to improve ICI efficacy. The online version contains supplementary material available at 10.1186/s13046-022-02337-x.