T cell exhaustion and accelerated aging is a hallmark of most tumor-specific T
cells, a critical component of the immune response to tumors. Tumorspecific
T cells may accumulate at tumor sites because they experience
migratory arrest and remain in proximity to tumor cells but are unable to
exert effective anti-tumor activity. Despite this pervasive exhaustion, TIL can
trigger objective clinical responses in a broad range of malignancies,
including breast, colon, bile duct, lung, and HPV-associated cancers. I will
review the cell intrinsic molecular and functional correlates of clinically
effective TIL. A deeper understanding of the qualities of clinically effective TIL
is guiding efforts to rejuvenate and re-functionalize these cells, which
includes epigenetic interventions and repair or replacement of dysfunctional
mitochondrial within TIL for use in treatment-refractory malignancies.