Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer.

Effector T cells and fibroblasts are major components in the tumor microenvironment. The means through which these cellular interactions affect chemoresistance is unclear. Here, we show that fibroblasts diminish nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy. We demonstrate that glutathione and cysteine released by fibroblasts contribute to this resistance. CD8(+) T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts. CD8(+) T-cell-derived interferon (IFN)γ controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyltransferases and transcriptional repression of system xc(-) cystine and glutamate antiporter via the JAK/STAT1 pathway. The presence of stromal fibroblasts and CD8(+) T cells is negatively and positively associated with ovarian cancer patient survival, respectively. Thus, our work uncovers a mode of action for effector T cells: they abrogate stromal-mediated chemoresistance. Capitalizing upon the interplay between chemotherapy and immunotherapy holds high potential for cancer treatment.

Fibroblasts from long-lived rodent species exclude cadmium.

Resistance to the lethal effects of cellular stressors, including the toxic heavy metal cadmium (Cd), is characteristic of fibroblast cell lines derived from long-lived bird and rodent species, as well as cell lines from several varieties of long-lived mutant mice. To explore the mechanism of resistance to Cd, we used inductively coupled plasma mass spectroscopy to measure the rate of Cd uptake into primary fibroblasts of 15 rodent species. These data indicate that fibroblasts from long-lived rodent species have slower rates of Cd uptake from the extracellular medium than those from short-lived species. In addition, fibroblasts from short-lived species export more zinc after exposure to extracellular Cd than cells from long-lived species. Lastly, fibroblasts from long-lived rodent species have lower baseline concentrations of two redox-active metals, iron and copper. Our results suggest that evolution of longevity among rodents required adjustment of cellular properties to alter metal homeostasis and to reduce the toxic effects of heavy metals that accumulate over the course of a longer life span.

Raman spectroscopy study of acid-base and structural properties of 9-[2-(phosphonomethoxy)ethyl]adenine in aqueous solutions.

The acid-base properties of the acyclic antiviral nucleotide analogue 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA) in aqueous solutions are studied by means of Raman spectroscopy in a pH range of 1-11 and compared with the properties of its common adenosine monophosphate counterparts (5'-AMP, 3'-AMP, and 2'-AMP). Factor analysis is used to separate the spectra of pure ionic species (PMEA2-, HPMEA-, H2PMEA, H3PMEA+) in order to determine their abundance, sites of protonation, and corresponding spectroscopic pK(a) values. The characteristic Raman features of the neutral adenine moiety in PMEA2- and HPMEA- species resemble those of neutral adenine in the AMPs, whereas significant differences are observed between the Raman spectra of the N1-protonated adenine of the solute zwitterionic H2PMEA and its N1-protonated AMP counterparts. On the contrary, the spectrum of crystalline H2PMEA, adopting an "anti-like" conformation, is found to be similar to the N1-protonated AMPs in solution. To explain peculiar Raman features a "syn-like" conformation is suggested for N1-protonated PMEA species in aqueous solutions instead of an anti-like one adopted by H2PMEA in crystals or by common AMPs in aqueous solutions. A physical mechanism of the anti-like to syn-like conformational transition of the solute PMEA that is due to adenine protonation and the flexibility of the (phosphonomethoxy)ethyl group is proposed and discussed.