Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non–small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.—Wang, M., Yao, L.-C., Cheng, M., Cai, D., Martinek, J., Pan, C.-X., Shi, W., Ma, A.-H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.
The RNA genome of coronaviruses consists of a single species of nonsegmented RNA. In this communication, we demonstrate that the RNA genomes of different strains of murine coronaviruses recombine during mixed infection at a very high frequency. Susceptible cells were coinfected with a temperature-sensitive mutant of one
We have isolated a recombinant virus between the A59 and JHM strains of mouse hepatitis virus, which contain a single species of nonsegmented RNA genome. This recombinant was derived by mixed infection of DBT cells with temperature-sensitive mutants of A59 and JHM at nonpermissive temperature. Viruses recovered at this temperature were screened by oligonucleotide fingerprinting of their genomic RNAs. One recombinant virus, B1, was found to contain mostly A59-derived sequences, but the 3 kilobases at the 5' end of the genomic RNA was derived from JHM. Thus, the crossover point in the B1 genome is located within gene A, which codes for the viral RNA polymerases. The study of the intracellular RNA species of BI virus revealed that probably all of the virus-specific subgenomic mRNA species contained the body sequences of strain A59 but the leader sequences of JHM. This result indicates that the JHM leader RNA, which differs from the A59 leader RNA, could be fused to the mRNAs of a different virus strain during RNA transcription. Furthermore, B1 virus-infected cells contain an additional subgenomic mRNA species which is transcribed from a new initiation site within gene C, suggesting that the leader RNA could determine the site of initiation for coronavirus mRNAs. These data represent a first report of RNA recombination between viruses, other than picornaviruses, which contain nonsegmented RNA genomes.
NF-KB is a potent inducible transcription factor that regulates many genes in activated T cells. In this report we examined the ability of different subunits of NF-KB to enhance HIV-1 transcription in vitro with chromatin templates. We find that the p65 subunit of NF-KB is a strong transcriptional activator of nucleosome-assembled HIV-1 DNA, whereas p50 does not activate transcription, and that p65 activates transcription synergistically with Spl and distal HIV-1 enhancer-binding factors (LEF-1, Ets-1, and TFE-3). These effects were observed with chromatin, but not with nonchromatin templates. Furthermore, binding of either p50 or p65 with Spl induces rearrangement of the chromatin to a structure that resembles the one reported previously for integrated HIV-1 proviral DNA in vivo. These results suggest that p50 and Spl contribute to the establishment of the nucleosomal arrangement of the uninduced provirus in resting T cells, and that p65 activates transcription by recruitment of the RNA polymerase II transcriptional machinery to the chromatin-repressed basal promoter.[Key Words: NF-KB; HIV-1 enhancer; chromatin structure; transcription] Received September 27, 1995; revised version accepted November 7, 1995.The NF-KB transcription factor is an important regulator of immune and inflammatory response genes in activated T cells. NF-KB exists in the nucleus as a mixture of various homo-and heterodimers of p65 (RelA) and p50 (KBF1)-related subunits (for recent reviews, see Baeuerle and Henkel 1994;Siebenlist et al. 1994;Miyamoto and Verma 1995). In resting cells, NF-KB proteins are sequestered in cytoplasmic complexes by interaction with members of the IKB inhibitory protein family. Activation of cells by a variety of inflammatory stimuli, including mitogens, cytokines, and oxidative stress, induces phosphorylation and degradation of the IKB proteins (Brown et al. 1995;Di Donato et al. 1995) and releases active NF-KB heterodimers, which translocate to the nucleus to stimulate transcription of responsive genes. Whereas homodimers of p50 appear to be the predominant form of NF-KB in resting cells, activated cells contain high levels of p50/p65 and related heterodimers, as well as homodimers of p65 (Ganchi et al. 1993). Transient expression assays reveal that the p65 subunit of NF-KB is responsible primarily for transcriptional activation by NF-KB (Schmitz and Baeuerle 1991;Ballard et al. 1992;Perkins et al. 1992), and a potent trans-activation domain was mapped to a carboxy-terminal region of p65 4These authors contributed equally to this work. 5Corresponding author.
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