The Immune System Strikes Back: Cellular Immune Responses against Indoleamine 2,3-dioxygenase

Background

The enzyme indoleamine 2,3-dioxygenase (IDO) exerts an well established immunosuppressive function in cancer. IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the present study, we tested the notion whether IDO itself may be subject to immune responses.

Methods and Findings

The presence of naturally occurring IDO-specific CD8 T cells in cancer patients was determined by MHC/peptide stainings as well as ELISPOT. Antigen specific cytotoxic T lymphocytes (CTL) from the peripheral blood of cancer patients were cloned and expanded. The functional capacity of the established CTL clones was examined by chrome release assays. The study unveiled spontaneous cytotoxic T-cell reactivity against IDO in peripheral blood as well as in the tumor microenvironment of different cancer patients. We demonstrate that these IDO reactive T cells are indeed peptide specific, cytotoxic effector cells. Hence, IDO reactive T cells are able to recognize and kill tumor cells including directly isolated AML blasts as well as IDO-expressing dendritic cells, i.e. one of the major immune suppressive cell populations.

Conclusion

IDO may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies. Furthermore, as emerging evidence suggests that IDO constitutes a significant counter-regulatory mechanism induced by pro-inflammatory signals, IDO-based immunotherapy holds the promise to boost anti-cancer immunotherapy in general.     

Influence of age and position on the CT number of adipose tissues in pigs

The location of adipose tissue depots is important in determining their significance. Research into the physical and chemical differences between these depots is therefore of interest. Using image analysis, this paper examines the influence of location on the linear attenuation coefficient of adipose tissue for X-rays, in computed tomography (as indicated by CT number) at three time points. Nine pigs were CT scanned on three separate occasions approximately 1 month apart. The mean CT number was -78, -100, and -104 for visceral adipose tissue (VAT) from the first to the final scan, respectively. The corresponding CT numbers for subcutaneous adipose tissue (SAT) were -80, -101, and -106. There was a significant difference between the CT numbers at each location at each scan (P values from 0.025 to <0.001) and between the CT numbers for each location at different times (P < 0.05). In a separate analysis of the final scan session, the mean CT number of adipose tissue at increasing distances from a mathematically defined center of the animal was determined. Regression analysis showed that the CT number of adipose tissue decreases with increasing distance from the animal's center (y = -102.7 - 0.04 x, P < 0.001, where y is the predicted CT number for adipose tissue, from the animal center (x = 0) to the skin (x = 100)). It can thus be expected that the overall mean CT number for adipose tissue can be used as an indicator of the relative quantities of adipose tissue at each location if the mean for each is known.     

Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue

Background We previously demonstrated that targeting lymphotoxin α (LTα) to the tumor evokes its immunological destruction in a syngeneic B16 melanoma model. Since treatment was associated with the induction of peritumoral tertiary lymphoid tissue, we speculated that the induced immune response was initiated at the tumor site. Methods and results In order to directly test this notion, we analyzed the efficacy of tumor targeted LTα in LTα knock-out (LTα^−/−) mice which lack peripheral lymph nodes. To this end, we demonstrate that tumor-targeted LTα mediates the induction of specific T-cell responses even in the absence of secondary lymphoid organs. In addition, this effect is accompanied by the initiation of tertiary lymphoid tissue at the tumor site in which B and T lymphocytes are compartmentalized in defined areas and which harbor expanded numbers of tumor specific T cells as demonstrated by in situ TRP-2/K^b tetramer staining. Mechanistically, targeted LTα therapy seems to induce changes at the tumor site which allows a coordinated interaction of immune competent cells triggering the induction of tertiary lymphoid tissue. Conclusion Thus, our data demonstrate that targeted LTα promotes an accelerated immune response by enabling the priming of T cells at the tumor site.     

Chronic activation of plasma renin is log-linearly related to dietary sodium and eliminates natriuresis in response to a pulse change in total body sodium

Responses to acute sodium loading depend on the load and on the level of chronic sodium intake. To test the hypothesis that an acute step increase in total body sodium (TBS) elicits a natriuretic response, which is dependent on the chronic level of TBS, we measured the effects of a bolus of NaCl during different low-sodium diets spanning a 25-fold change in sodium intake on elements of the renin-angiotensin-aldosterone system (RAAS) and on natriuresis. To custom-made, low-sodium chow (0.003%), NaCl was added to provide four levels of intake, 0.03-0.75 mmol.kg(-1).day(-1) for 7 days. Acute NaCl administration increased PV (+6.3-8.9%) and plasma sodium concentration (~2%) and decreased plasma protein concentration (-6.4-8.1%). Plasma ANG II and aldosterone concentrations decreased transiently. Potassium excretion increased substantially. Sodium excretion, arterial blood pressure, glomerular filtration rate, urine flow, plasma potassium, and plasma renin activity did not change. The results indicate that sodium excretion is controlled by neurohumoral mechanisms that are quite resistant to acute changes in plasma volume and colloid osmotic pressure and are not down-regulated within 2 h. With previous data, we demonstrate that RAAS variables are log-linearly related to sodium intake over a >250-fold range in sodium intake, defining dietary sodium function lines that are simple measures of the sodium sensitivity of the RAAS. The dietary function line for plasma ANG II concentration increases from theoretical zero at a daily sodium intake of 17 mmol Na/kg (intercept) with a slope of 16 pM increase per decade of decrease in dietary sodium intake.     

Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer

ErbB receptors (EGFR (ErbB1), ErbB2, ErbB3, and ErbB4) are important regulators of normal growth and differentiation, and they are involved in the pathogenesis of cancer. Following ligand binding and receptor activation, EGFR is endocytosed and transported to lysosomes where the receptor is degraded. This downregulation of EGFR is a complex and tightly regulated process. The functions of ErbB2, ErbB3, and ErbB4 are also regulated by endocytosis to some extent, although the current knowledge of these processes is sparse. Impaired endocytic downregulation of signaling receptors is frequently associated with cancer, since it can lead to increased and uncontrolled receptor signaling. In this review we describe the current knowledge of ErbB receptor endocytic downregulation. In addition, we outline how ErbB receptors can escape endocytic downregulation in cancer, and we discuss how targeted anti-cancer therapy may induce endocytic downregulation of ErbB receptors.