PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity.

Immunotherapies aimed at alleviating the inhibitory constraints on T cells have revolutionized cancer management. To date, these have focused on the blockade of cell-surface checkpoints such as PD-1. Herein we identify protein tyrosine phosphatase 1B (PTP1B) as an intracellular checkpoint that is upregulated in T cells in tumors. We show that increased PTP1B limits T-cell expansion and cytotoxicity to contribute to tumor growth. T cell-specific PTP1B deletion increased STAT5 signaling, and this enhanced the antigen-induced expansion and cytotoxicity of CD8+ T cells to suppress tumor growth. The pharmacologic inhibition of PTP1B recapitulated the T cell-mediated repression of tumor growth and enhanced the response to PD-1 blockade. Furthermore, the deletion or inhibition of PTP1B enhanced the efficacy of adoptively transferred chimeric antigen receptor (CAR) T cells against solid tumors. Our findings identify PTP1B as an intracellular checkpoint whose inhibition can alleviate the inhibitory constraints on T cells and CAR T cells to combat cancer. SIGNIFICANCE: Tumors subvert antitumor immunity by engaging checkpoints that promote T-cell exhaustion. Here we identify PTP1B as an intracellular checkpoint and therapeutic target. We show that PTP1B is upregulated in intratumoral T cells and that its deletion or inhibition enhances T-cell antitumor activity and increases CAR T-cell effectiveness against solid tumors. This article is highlighted in the In This Issue feature, p. 587.

7,8-Dihydroxyflavone Enhances Cue-Conditioned Alcohol Reinstatement in Rats.

Alcohol use disorder (AUD) is a detrimental disease that develops through chronic ethanol exposure. Reduced brain-derived neurotrophic factor (BDNF) expression has been associated with AUD and alcohol addiction, however the effects of activation of BDNF signalling in the brain on voluntary alcohol intake reinstatement and relapse are unknown. We therefore trained male and female Sprague Dawley rats in operant chambers to self-administer a 10% ethanol solution. Following baseline acquisition and progressive ratio (PR) analysis, rats were split into drug and vehicle groups during alcohol lever extinction. The animals received two weeks of daily IP injection of either the BDNF receptor, TrkB, agonist, 7,8-dihydroxyflavone (7,8-DHF), or vehicle. During acquisition of alcohol self-administration, males had significantly higher absolute numbers of alcohol-paired lever presses and a higher PR breakpoint. However, after adjusting for body weight, the amount of ethanol was not different between the sexes and the PR breakpoint was higher in females than males. Following extinction, alcohol-primed reinstatement in male rats was not altered by pretreatment with 7,8-DHF when adjusted for body weight. In contrast, in female rats, the weight-adjusted potential amount of ethanol, but not absolute numbers of active lever presses, was significantly enhanced by 7,8-DHF treatment during reinstatement. Analysis of spontaneous locomotor activity in automated photocell cages suggested that the effect of 7,8-DHF was not associated with hyperactivity. These results suggest that stimulation of the TrkB receptor may contribute to reward craving and relapse in AUD, particularly in females.

Brain-derived neurotrophic factor (BDNF) determines a sex difference in cue-conditioned alcohol seeking in rats.

Alcohol use disorder is a detrimental addictive disease that develops through prolonged ethanol exposure and regular intoxication. However, the changes in the underlying neurobiology leading to alcohol addiction remain unclear. Brain-Derived Neurotrophic Factor (BDNF) is implicated in substance abuse disorders including alcoholism. As the vast majority of previous animal model studies have concentrated on males only, the aim of this study was to determine whether endogenous BDNF mediates alcohol seeking in a sex-specific manner. We used an operant self-administration paradigm where the animals were trained in operant chambers to self-administer a 10% ethanol solution, and compared male and female BDNF heterozygous (HET) and wildtype (WT) rats. Over several weeks, the animals progressed through acquisition, progressive ratio, extinction, and reinstatement phases. There were no significant sex or genotype differences in the number of alcohol-paired lever presses during acquisition, progressive ratio and extinction. However, a significant difference between male and female WT rats following alcohol-primed reinstatement was completely absent in BDNF HET rats suggesting a role of BDNF in sex differences in alcohol seeking after abstinence. Female BDNF HET rats showed significantly higher number of alcohol-paired lever presses during reinstatement than female WT controls. These findings suggest that BDNF regulatory pathways are involved in sex differences in reinstatement of alcohol intake and emphasize the need to include both male and female animals to explore sex-specific interactions in addiction neurocircuitry.