Jahangir Arthee, Chandra Dinesh, Quispe-Tintaya Wilber, Singh Manisha, Selvanesan Benson Chellakkan, Gravekamp Claudia
Albert Einstein College of Medicine, Department of Microbiology and Immunology, 1300 Morris Park Avenue, Bronx, NY, USA.
Oncoimmunology. 2017 Jul 5;6(9):e1342025. doi: 10.1080/2162402X.2017.1342025. eCollection 2017.
Cancer immunotherapy is one of the most promising and benign therapies against metastatic cancer. However, most cancer patients are old and elderly react less efficient to cancer vaccines than young adults, due to T cell unresponsiveness. Here we present data of cancer vaccination in young and old mice with metastatic breast cancer (4T1 model). We tested adaptive and innate immune responses to foreign antigens (Listeria-derived) and self-antigens (tumor-associated antigens (TAA)) and their contribution to elimination of metastases at young and old age. Three different protocols were tested with Listeria: a semi- and exclusive-therapeutic protocol both one-week apart, and an exclusive therapeutic protocol frequently administered. Adaptive and innate immune responses were measured by ELISPOT in correlation with efficacy in the 4T1 model. We found that Listeria induced immunogenic tumor cell death, resulting in CD8 T cell responses to multiple TAA expressed by the 4T1 tumors. Only exclusive therapeutic frequent immunizations were able to overcome immune suppression and to activate TAA- and Listeria-specific CD8 T cells, in correlation with a strong reduction in metastases at both ages. However, MHC class Ia antibodies showed inhibition of CD8 T cell responses to TAA at young but not at old age, and CD8 T cell depletions demonstrated that the T cells contributed to reduction in metastases at young age only. These results indicate that CD8 T cells activated by Listeria has an antitumor effect at young but not at old age, and that metastases at old age have been eliminated through different mechanism(s).
癌症免疫疗法是针对转移性癌症最有前景且最温和的疗法之一。然而，大多数癌症患者年事已高，由于T细胞无反应性，老年人对癌症疫苗的反应不如年轻人有效。在此，我们展示了用转移性乳腺癌（4T1模型）对年轻和年老小鼠进行癌症疫苗接种的数据。我们测试了对异体抗原（源自李斯特菌）和自身抗原（肿瘤相关抗原（TAA））的适应性和先天性免疫反应，以及它们在年轻和年老时对消除转移灶的作用。用李斯特菌测试了三种不同方案：一种半治疗性和一种排他性治疗方案，间隔均为一周，以及一种频繁给药的排他性治疗方案。通过ELISPOT测量适应性和先天性免疫反应，并与4T1模型中的疗效相关联。我们发现，李斯特菌诱导免疫原性肿瘤细胞死亡，导致CD8 T细胞对4T1肿瘤表达的多种TAA产生反应。只有频繁给药的排他性治疗能够克服免疫抑制并激活TAA特异性和李斯特菌特异性CD8 T细胞，这与两个年龄段转移灶的显著减少相关。然而，MHC I类抗体在年轻时显示出对CD8 T细胞对TAA反应的抑制作用，而在老年时则无此作用，并且CD8 T细胞耗竭表明T细胞仅在年轻时对转移灶的减少有作用。这些结果表明，由李斯特菌激活的CD8 T细胞在年轻时具有抗肿瘤作用，而在老年时则无，并且老年时转移灶的消除是通过不同机制实现的。
