Abstract
The immune system, and in particular, cytotoxic CD8+ T cells (CTLs), plays a vital part in the prevention and elimination of tumors. In many patients, however, CTL-mediated tumor killing ultimately fails in the clearance of cancer cells resulting in disease progression, in large part due to the progression of effector CTL into exhausted CTL. While there have been major breakthroughs in the development of CTL-mediated “reinvigoration”-driven immunotherapies such as checkpoint blockade therapy, there remains a need to better understand the drivers behind the development of T cell exhaustion. Our study highlights the unique differences in T cell exhaustion development in tumor-specific CTL which arises over time in a mouse model of mesothelioma. Importantly, we also show that peripheral tumor-specific T cells have a unique expression profile compared to exhausted tumor-infiltrating CTL at a late-stage of tumor progression in mice. Together, these data suggest that greater emphasis should be placed on understanding contributions of individual microenvironments in the development of T cell exhaustion.
Highlights
With more than 1.5 million new cancer diagnoses annually in the US alone and increased numbers worldwide, cancer remains a major public health concern with high incidences of morbidity and mortality
We found that subcutaneous injection of 5 × 105 AE17sOVA into the hind-flank of adult female wild-type mice that had received an injection of 1 × 104 OT-I CD8+ T cells 3 h prior resulted in the reproducible growth of vascularized tumors (Figure 1A)
Donor cells were identified by the congenic marker CD45.1 and an appreciable endogenous CD8+ T cell response was detected by tetramer staining of CD45.1− OVA(257−264)-specific CTL (Figure 1B)
Summary
With more than 1.5 million new cancer diagnoses annually in the US alone and increased numbers worldwide, cancer remains a major public health concern with high incidences of morbidity and mortality. CTL-mediated tumor killing fails in the clearance of cancer cells resulting in disease progression. CTL exhaustion is a cell-intrinsic alteration resulting in decreased functionality and effector capabilities as well as depressed proliferative capacity and Microenvironment-Dependent CTL Exhaustion increased apoptosis of the cell. This exhaustion has been shown to be induced by chronic antigen stimulation and is primarily mediated by T cell receptor (TCR) stimulation [1, 2]. The exhausted cell becomes proapoptotic and is prone to activation-induced cell death upon TCR engagement or Fas-mediated apoptosis [4, 5]
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