Abstract
Tumor-infiltrating CD8+ T cells (TIL) are of the utmost importance in anti-tumor immunity. CD103 defines tumor-resident memory T cells (TRM cells) associated with improved survival and response to immune checkpoint blockade (ICB) across human tumors. Co-expression of CD39 and CD103 marks tumor-specific TRM with enhanced cytolytic potential, suggesting that CD39+CD103+ TRM could be a suitable biomarker for immunotherapy. However, little is known about the transcriptional activity of TRM cells in situ. We analyzed CD39+CD103+ TRM 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+ TRM cells were transcriptionally active and expressed a characteristic TRM signature. Activated CD39+CD103+ TRM 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+ TRM cells are transcriptionally active TRM cells with a polyfunctional, reactivation-responsive repertoire. Secondly, we hypothesize that differential regulation of transcript stability potentiates rapid responses upon TRM reactivation in tumors.
Highlights
The influence of tumor-infiltrating lymphocytes (TIL) on cancer prognosis is widely recognized, and TIL are studied in a wide variety of solid tumors
In this study we showed that resting CD39+CD103+ TRM cells were transcriptionally active and expressed a characteristic tissue-resident transcriptional profile
We showed that resting CD39+CD103+ TRM cells were transcriptionally active and expressed a characteristic tissue-resident transcriptional profile comparable to TRM in other tumor types [31]
Summary
The influence of tumor-infiltrating lymphocytes (TIL) on cancer prognosis is widely recognized, and TIL are studied in a wide variety of solid tumors. POLE-mutant and dMMR tumors harbor many neoantigens and are more infiltrated by immune cells, including CD103+ TRM [16,17,18]. A further specification of TRM cells in endometrial cancer might be relevant, as CD39 and CD103 co-expression identifies tumor-resident, clonally expanded, tumor antigen-specific T cells with superior cytolytic capacity [19,20]. Tumor-resident CD103+ TRM differentially express immune checkpoints such as CTLA4, TIM3, LAG3, and TIGIT, indicating T cell exhaustion due to excess antigen stimulation [9,18,19,26]. We studied the transcriptional profile of high-grade endometrial cancer CD39+CD103+ TRM cells in situ, after T cell activation, and after transcriptional inhibition with actinomycin D in order to elucidate core elements necessary for successful T cell reactivation. We studied transcript stability and found that PMA-responsive immune genes and mitochondrial genes were stable, which led us to hypothesize this differential regulation of transcript stability potentiates rapid responses upon TRM reactivation in tumors
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