Systemic delivery of a targeted synthetic immunostimulant transforms the immune landscape for effective tumor regression.
Systemic delivery of a targeted synthetic immunostimulant transforms the immune landscape for effective tumor regression.
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靶向合成免疫刺激剂的全身递送改变了有效肿瘤消退的免疫景观。
DOI：
10.1016/j.chembiol.2021.10.012
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发表时间：
2022-03-17
影响因子：
8.6
通讯作者：
Cochran, Jennifer R.
中科院分区：
文献类型：
--
作者：
Miller, Caitlyn L.;Sagiv-Barfi, Idit;Neuhofer, Patrick;Czerwinski, Debra K.;Artandi, Steven E.;Bertozzi, Carolyn R.;Levy, Ronald;Cochran, Jennifer R.
在肿瘤微环境（TME）内促进免疫激活是逆转肿瘤免疫抑制并引发抗肿瘤免疫的有前景的治疗策略。为了在静脉内给药后实现肿瘤局部免疫治疗，我们将多特异性整合素结合肽（PIP）与免疫刺激剂（TLR 9激动剂：CpG）化学缀合以产生肿瘤靶向免疫调节剂，称为PIP-CpG。我们证明，在侵袭性鼠乳腺癌和胰腺癌模型中，与非靶向CpG相比，PIP-CpG的全身递送诱导肿瘤消退并增强治疗功效。此外，PIP-CpG将由骨髓来源的抑制细胞支配的免疫抑制性TME转化为浸润有活化的CD 8 + T细胞、CD 4 + T细胞和B细胞的富含淋巴细胞的TME。最后，我们表明T细胞是治疗功效所必需的，并且PIP-CpG治疗产生肿瘤特异性CD 8 + T细胞。这些数据表明，与合成的肿瘤靶向肽缀合可以改善全身施用的免疫刺激剂的功效并导致持久的抗肿瘤免疫应答。为了将免疫疗法递送至肿瘤，米勒等人将免疫刺激性TLR 9激动剂缀合至体内定位于肿瘤的独特整联蛋白结合肽。这种肿瘤靶向免疫刺激剂的全身给药改变了肿瘤免疫微环境，并导致小鼠中免疫介导的肿瘤消退。
Promoting immune activation within the tumor microenvironment (TME) is a promising therapeutic strategy to reverse tumor immunosuppression and elicit anti-tumor immunity. To enable tumor-localized immunotherapy following intravenous administration, we chemically conjugate a polyspecific integrin-binding peptide (PIP) to an immunostimulant (TLR9 agonist: CpG) to generate a tumor-targeted immunomodulatory agent, referred to as PIP-CpG. We demonstrate that systemic delivery of PIP-CpG induces tumor regression and enhances therapeutic efficacy compared to untargeted CpG in aggressive murine breast and pancreatic cancer models. Furthermore, PIP-CpG transforms the immune-suppressive TME dominated by myeloid-derived suppressor cells into a lymphocyte-rich TME infiltrated with activated CD8+ T cells, CD4+ T cells, and B cells. Finally, we show that T cells are required for therapeutic efficacy and that PIP-CpG treatment generates tumor-specific CD8+ T cells. These data demonstrate that conjugation to a synthetic tumor-targeted peptide can improve the efficacy of systemically-administered immunostimulants and lead to durable anti-tumor immune responses. To deliver immunotherapy to tumors, Miller et al. conjugate an immune-stimulating TLR9 agonist to a unique integrin-binding peptide that localizes to tumors in vivo. Systemic administration of this tumor-targeted immunostimulant transforms the tumor immune microenvironment and results in immune-mediated tumor regression in mice.
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影响因子：
2.9
作者：
Kimura RH;Levin AM;Cochran FV;Cochran JR
通讯作者：
Cochran JR
影响因子：
7.3
作者：
Kawasaki T;Kawai T
通讯作者：
Kawai T
影响因子：
4.8
作者：
Khan, Selina;Bijker, Martijn S.;Ossendorp, Ferry
通讯作者：
Ossendorp, Ferry
影响因子：
5.5
作者：
Daftarian, P;Sharan, R;Diamond, DJ
通讯作者：
Diamond, DJ
DOI：
10.1002/anie.201603488
发表时间：
2016-08-16
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Cox N;Kintzing JR;Smith M;Grant GA;Cochran JR
通讯作者：
Cochran JR