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Tumor-infiltrating CD8+ T cells (TIL) are of the utmost importance in anti-tumor immunity. CD103 defines tumor-resident memory T cells (T RM cells) associated with improved survival and response to immune checkpoint blockade (ICB) across human tumors. Co-expression of CD39 and CD103 marks tumor-specific T RM with enhanced cytolytic potential, suggesting that CD39+CD103+ T RM could be a suitable biomarker for immunotherapy. However, little is known about the transcriptional activity of T RM cells in situ. We analyzed CD39+CD103+ T RM cells sorted from human high-grade endometrial cancers ( n = 3) using mRNA sequencing. Cells remained untreated or were incubated with PMA/ionomycin (activation), actinomycin D (a platinum-like chemotherapeutic that inhibits transcription), or a combination of the two. Resting CD39+CD103+ T RM cells were transcriptionally active and expressed a characteristic T RM signature. Activated CD39+CD103+ T RM cells differentially expressed PLEK , TWNK , and FOS , and cytokine genes IFNG , TNF , IL2 , CSF2 (GM-CSF), and IL21 . Findings were confirmed using qPCR and cytokine production was validated by flow cytometry of cytotoxic TIL. We studied transcript stability and found that PMA-responsive genes and mitochondrial genes were particularly stable. In conclusion, CD39+CD103+ T RM cells are transcriptionally active T RM cells with a polyfunctional, reactivation-responsive repertoire. Secondly, we hypothesize that differential regulation of transcript stability potentiates rapid responses upon T RM reactivation in tumors.

Transcriptional Activity and Stability of CD39+CD103+CD8+ T Cells in Human High-Grade Endometrial Cancer