清除近一半的肿瘤！损伤的肿瘤细胞可成为除瘤武器！科学家发现唤醒免疫系统的新方法！

2021-10-27 梅斯医学 MedSci原创

_Shirley

企业/

为了避免造成体内免疫细胞受损，研究人员将肿瘤细胞离体培养并处理后将这些肿瘤细胞注射到体内肿瘤中，除了约40%的小鼠肿瘤，并且小鼠的存活率也显著提高了，至少 98 天内保持无瘤！

我们都知道，肿瘤会逃避免疫系统的识别攻击，从而不断增殖。肿瘤细胞附近的免疫细胞如树突细胞，作为功能最强大的抗原递呈细胞，可能认不出肿瘤细胞，而主要的杀伤性细胞T细胞毒性细胞常常被肿瘤细胞折腾的不堪重负、精疲力竭，对肿瘤造不成任何威胁。

如何重新唤醒这些肿瘤附近的免疫细胞，让它们再次满血杀敌呢？麻省理工学院的研究人员想到——如果肿瘤细胞受伤了呢？是否会引起免疫系统的注意？

于是，他们将受伤的癌细胞输注到小鼠体内，结果发现，受伤的肿瘤细胞确实会引起免疫系统的注意，并能重新唤醒免疫系统满血复活去杀敌，清除了将近一半患癌小鼠的肿瘤。该研究结果最近发表在了《Science Signaling》上。

首先，研究人员用化疗药物Etoposide或mitoxantrone来处理体外的肿瘤细胞，创造出有DNA损伤但是没有被杀死的肿瘤细胞。

为什么要在体外创造损伤的肿瘤细胞呢？体内直接注射化疗药物也一样会造成肿瘤细胞受伤，不是更方便吗？

这是因为，体内直接注射化疗药物联合全身性免疫给药，并没有提高患瘤小鼠的生存率。研究人员观察到，树突细胞和T细胞共同暴露于Etoposide，会导致T细胞严重受损，树突细胞生存能力显著削弱。

这也许解释了为什么很多病人在化疗和免疫联合疗法中会出现进展疾病，即病情越来越严重，状况恶化的情况。体内直接给化疗药物，虽然也能让肿瘤细胞受损，但同时也会让免疫细胞受伤。

因此，为了避免造成体内免疫细胞受损，研究人员将肿瘤细胞离体培养后用Etoposide处理，洗掉药物后再将这些受损伤的肿瘤细胞注射到体内肿瘤中，联合全身性免疫检查点阻断剂 (ICB)给药。

结果发现，这种方法清除了约40%的小鼠肿瘤，并且小鼠的存活率也显著提高了，至少 98 天内保持无瘤！表明化疗受损的肿瘤细胞可作为一种有效的免疫增强剂，与免疫治疗药物结合，能有效地激活T 细胞清除肿瘤。

更令人激动的是，研究人员在这些已经消除了肿瘤的小鼠体内再次接种活的肿瘤细胞，想知道这些已经治愈的小鼠会不会再次长出肿瘤。

结果发现，他们均未再次发展成肿瘤，且在这些小鼠体内都观察到了大量的T毒性细胞，而在未长过肿瘤的小鼠体内接种活的肿瘤细胞，则30天内都长出了肿瘤，在它们的体内也没有观察到T毒性细胞。

这表明，化疗受损肿瘤细胞作为佐剂与全身性免疫检查点阻断剂给药相结合，可诱导抗肿瘤免疫记忆，当这些小鼠体内再次遇到癌细胞时，T细胞会识别它们并在它们形成新的肿瘤之前摧毁它们。

以上实验是研究人员在小鼠黑色素瘤和结肠癌中完成的，化疗受损肿瘤细胞佐剂联合ICB的治疗方案都显示出了完全的肿瘤清除能力以及抵抗活肿瘤细胞的再次攻击，证明这种方法不仅限于一种肿瘤细胞类型。

来自患者肿瘤活检的肿瘤细胞经过化疗损伤也可作为清除肿瘤的武器，联合全身性免疫检查点阻断剂给药这种方法有可能适用于肿瘤内给药、常规治疗方案失败且 ICB 初始抗药或获得性耐药的患者。

参考文献：The injury response to DNA damage in live tumor cells promotes antitumor immunity, Sriram et al., Sci. Signal. 14, eabc4764 (2021). DOI: 10.1126/scisignal.abc4764

撰文 | lcy

编辑 | Jennie

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2022-09-26 旅苦化文_208

#科学家发现#

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2022-07-23 kord1982

#新方法#

30 0
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2021-10-29 hmwwww

#肿瘤细胞#

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2021-10-29 ms3046638856685384

#损伤#

30 0
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2021-10-27 145b2d07m08暂无昵称

厉害

63 0
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2021-10-27 ms6000000177538915

学习了

52 0
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2021-10-27 jiazhoudexue

good idea

65 0

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