Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance.

IF 6.5 2区 医学 Q1 IMMUNOLOGY Oncoimmunology Pub Date : 2024-03-20 eCollection Date: 2024-01-01 DOI:10.1080/2162402X.2024.2330194
Reshmi Nair, Tamsin R M Lannagan, Rene Jackstadt, Anna Andrusaite, John Cole, Caitlin Boyne, Robert J B Nibbs, Owen J Sansom, Simon Milling
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Abstract

Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20-30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), "KPN", which resembles the human 'CMS4'-like subtype. We show here that transforming growth factor (TGF-β1), secreted by KPN organoids, increases cancer cell proliferation, and inhibits splenocyte activation in vitro. TGF-β1 also inhibits activation of naive but not pre-activated T cells, suggesting differential effects on specific immune cells. In vivo, the inhibition of TGF-β inflames the KPN tumors, causing infiltration of T cells, monocytes and monocytic intermediates, while reducing neutrophils and epithelial cells. Co-inhibition of TGF-β and PD-L1 signaling further enhances cytotoxic CD8+T cells and upregulates innate immune response and interferon gene signatures. However, simultaneous upregulation of cancer-related metabolic genes correlated with limited control of tumor burden and/or progression despite combination treatment. Our study illustrates the importance of using GEMMs to predict better immunotherapies for mCRC.

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在转移性结直肠癌小鼠模型中共同抑制 TGF-β 和 PD-L1 通路,可引发干扰素反应、先天性细胞和 T 细胞,以及代谢变化和肿瘤抗药性。
结直肠癌(CRC)是全球发病率第三高的癌症,死亡率很高(20%-30%),尤其是由于邻近器官的转移。化疗、放疗、靶向治疗和免疫治疗的临床反应仅限于部分患者,这使得转移性 CRC(mCRC)难以治疗。为了了解对 mCRC 免疫反应的治疗调节,我们使用了一种基因工程小鼠模型(GEMM)--"KPN",它类似于人类的 "CMS4 "类亚型。我们在此表明,KPN 器官组织分泌的转化生长因子(TGF-β1)可增加癌细胞增殖,并抑制体外脾细胞活化。TGF-β1 还能抑制幼稚 T 细胞的活化,但不能抑制预活化 T 细胞的活化,这表明它对特异性免疫细胞有不同的作用。在体内,抑制 TGF-β 可使 KPN 肿瘤发炎,导致 T 细胞、单核细胞和单核细胞中间产物浸润,同时减少中性粒细胞和上皮细胞。联合抑制 TGF-β 和 PD-L1 信号可进一步增强细胞毒性 CD8+T 细胞,并上调先天性免疫反应和干扰素基因特征。然而,尽管进行了联合治疗,癌症相关代谢基因的同时上调与肿瘤负荷和/或进展的有限控制相关。我们的研究说明了利用GEMM预测更好的mCRC免疫疗法的重要性。
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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
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