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

Abstract

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