Biology subjects

Lopez-Rodriguez, C.

Publications and source records attributed to Lopez-Rodriguez, C..

3 recordsLinked to original sources

bioRxiv2024

Effector T cells in poorly perfused tumor regions exhibit a distinct signature of augmented IFN response and reduced PD-1 expression

Effector T lymphocytes are avid glucose consumers, but can function in the nutrient-poor environments of tumors. However, availability of blood-delivered nutrients throughout the tumor is not homogeneous, and how this affects effector T cells is not well known. Here we have isolated tumor-infiltrating T lymphocytes (TILs) from mouse solid tumors by their capacity to capture blood-transported probes, and compared them with glucose-restricted T cells. Glucose restriction in vitro arrested cell proliferation but reduced only moderately the induction of hallmark glucose-dependent cytokines interferon gamma (IFN{gamma}) and IL-17. In vivo, effector TILs with reduced access to blood had characteristics of glucose-restricted cells, such as reduced expression of IFN{gamma} and genes associated with cell proliferation. However, they expressed more CXCR3, which identifies effective antitumor T lymphocytes, showed an enhanced IFN response signature, and had reduced expression of surface PD-1. We also identified genes regulated by the enzyme ACSS2, which allows TILs to sustain gene expression in glucose-poor environments. Thus, effector T lymphocytes infiltrating tumors express different gene signatures in regions with different accessibility to blood, and can maintain specific glucose-dependent responses even in poorly perfused tumor regions. Our results can help better understand nutrient-dependent TIL heterogeneity in changing tumor microenvironments. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/601540v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@115d6beorg.highwire.dtl.DTLVardef@c56904org.highwire.dtl.DTLVardef@71b324org.highwire.dtl.DTLVardef@a804d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

NFAT5 induction by the tumor microenvironment enforces CD8 T cell exhaustion

Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. We discovered that NFAT5, an NFAT family member lacking an AP-1 docking site, is highly expressed in exhausted T cells from murine and human tumors and is a central player in tumor-induced exhaustion. While NFAT5 overexpression reduced tumor control, NFAT5 deletion improved tumor control by promoting the accumulation of tumor-specific CD8+ T cells that expressed less TOX and PD-1 and produced more cytokines particularly among precursor exhausted cells. Conversely, NFAT5 had no effect on chronic infection-induced T cell exhaustion. Mechanistically we found that TCR triggering induced NFAT5 expression and that hyperosmolarity stimulated transcriptional activity of NFAT5. We propose that NFAT5 takes over NFAT1/2 to promote exhaustion specifically in tumor-infiltrating CD8+ T cells.

immunology↗

bioRxiv2018

Analgesia linked to Nav1.7 loss of function requires mu and delta opioid receptors

Functional deletion of the SCN9A gene encoding sodium channel Nav1.7 makes humans and mice pain-free (1,2). Opioid signaling contributes to this analgesic state (3). Here we show that the pharmacological block or deletion of both and {delta} opioid receptors is required to abolish Nav1.7 null opioid-related analgesia.{kappa}-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls (3). Deleting Nfat5, a transcription factor with binding motifs upstream of Penk (4), induces the same level of enkephalin mRNA expression as found in Nav1.7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to SCN9A gene loss is required for analgesia. Higher levels of endogenous enkephalins (3), potentiated opioid receptors (5), diminished electrical excitability (6,7) and loss of neurotransmitter release (2,1) together contribute to the analgesic phenotype found in Nav1.7 null mouse and human mutants. These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.

neuroscience↗