PO.IM01.11 · 免疫学
阐明CD4+ T细胞使间充质型CD73缺陷肿瘤对抗CTLA4免疫检查点阻断治疗敏感的机制
Understanding the mechanism by which CD4 + T cells sensitize mesenchymal CD73-deficient tumors to anti-CTLA4 immune checkpoint blockade therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌(TNBC)是一种高度侵袭性疾病，由于其对化疗和免疫治疗的耐药性，患者预后较差。尽管免疫检查点阻断(ICB)治疗在黑色素瘤和肺癌中疗效显著，但仅对极少数TNBC患者有效。上皮-间充质转化(EMT)是恶性进展的关键驱动因素，可导致更强的转移潜能和免疫抑制性肿瘤微环境，从而驱动对治疗的耐药。我们此前的结果表明，上皮型肿瘤对抗CTLA4治疗有反应，而间充质型肿瘤则耐药。值得注意的是，在间充质型肿瘤中敲除CD73可使其对抗CTLA4治疗完全敏感，但对临床更常用的抗PD1治疗则不然。我们利用临床前小鼠模型结合免疫荧光染色发现，与无反应对照相比，CD73缺陷型肿瘤在抗CTLA4治疗后表现出CD4+和CD8+ T细胞浸润增加。最引人注目的是，尽管CD73缺陷型肿瘤在缺乏CD8+ T细胞的情况下仍持续对抗CTLA4治疗有反应，但在缺乏CD4+ T细胞时却无反应。然而，CD4+ T细胞促进间充质型肿瘤清除的机制仍不清楚。初步结果表明，细胞毒性CD4+ T细胞在增强CD73缺陷型肿瘤对抗CTLA4的反应中发挥关键作用。此外，肿瘤中含有可塑性CD4+ T细胞亚群，其在抗CTLA4治疗下减弱免疫抑制，而在抗PD1治疗下促进免疫抑制。这些结果揭示，CD4+ T细胞能够特异性靶向致命的间充质型癌细胞，以响应抗CTLA4治疗而非抗PD1治疗。鉴于抗PD1治疗在TNBC临床试验中的无效性，表征CD4+ T细胞对抗CTLA4的反应为发挥其治疗潜能提供了机制基础。
查看英文原文 English abstract
Triple-Negative Breast Cancer (TNBC) is a highly aggressive disease with poor patient outcomes due to its resistance to chemotherapy and immunotherapy. Despite its efficacy in Melanoma and Lung carcinoma, immune checkpoint blockade (ICB) therapy is only effective in a small minority of TNBC patients. Epithelial-to-Mesenchymal Transition (EMT) is a key driver of malignant progression leading to greater metastatic potential and an immunosuppressive tumor microenvironment, driving resistance to therapies. Our previous results demonstrate that epithelial tumors respond to anti-CTLA4 therapy while mesenchymal tumors are resistant. Strikingly, knockout of CD73 in mesenchymal tumors results in complete sensitization to anti-CTLA4 treatment but not anti-PD1 therapy, the more clinically used treatment. Using our preclinical mouse models together with immunofluorescence staining, we observed that CD73-deficient tumors display increased infiltration of CD4 + and CD8 + T cells upon anti-CTLA4 treatment relative to non-responding controls. Most notably, while CD73 deficient tumors continued to respond to anti-CTLA4 treatment without CD8 + T cells, they failed to respond in the absence of CD4 + T cells. However, the mechanisms by which CD4 + T cells facilitate the elimination of mesenchymal tumors remain unknown. Preliminary results demonstrate that cytotoxic CD4 + T cells play a crucial role in potentiating the response of CD73-deficient tumors to anti-CTLA4. Moreover, tumors contain plastic CD4 + T cell subsets that reduce immune suppression under anti-CTLA4 treatment while promoting immune suppression under anti-PD1 treatment. These results reveal that CD4 + T cells can specifically target lethal mesenchymal cancer cells in response to anti-CTLA4 but not anti-PD1 therapy. Future work is aimed at understanding whether CD4 + T cells eliminate tumors via direct interactions with cancer cells or through indirect activation of other immune cells. Given the inefficacy of anti-PD1 therapy in TNBC clinical trials, characterizing the CD4 + T cell response to anti-CTLA4 provides a mechanistic basis for leveraging its therapeutic potential.
利益披露 Disclosure
B. H. Feng, None..
I. O'Connell, None..
S. Chandraganti, None..
A. Dongre, None.