Immunotherapy has revolutionized the treatment of cancer.Nevertheless, the majority of patients do not respond to therapy, meaning a deeper understanding of tumor immune evasion strategies is required to boost treatment efficacy.The vast majority of immunotherapy studies have focused on how treatment reinvigorates exhausted CD8+ T cells within the tumor.
In contrast, how therapies influence regulatory processes Elderberry / Sambucus within the draining lymph node is less well studied.In particular, relatively little has been done to examine how tumors may exploit peripheral CD8+ T cell tolerance, an under-studied immune checkpoint that under normal circumstances prevents detrimental autoimmune disease by blocking the initiation of T cell responses.Here we review the therapeutic potential of blocking peripheral CD8+ T cell tolerance for the treatment of cancer.
We first comprehensively review what has been learnt about the regulation of CD8+ T cell peripheral tolerance from the non-tumor models in which peripheral tolerance was first defined.We next consider how the tolerant state differs from other states of negative regulation, such as T cell exhaustion and senescence.Finally, we describe how tumors hijack the peripheral tolerance immune checkpoint to prevent anti-tumor immune responses, and argue that disruption of peripheral Bathroom tolerance may contribute to both the anti-cancer efficacy and autoimmune side-effects of immunotherapy.
Overall, we propose that a deeper understanding of peripheral tolerance will ultimately enable the development of more targeted and refined cancer immunotherapy approaches.