CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1.

The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.

Transgenic HPV11-E2 protein modulates URR activity in vivo.

In vitro experiments have shown that the E2 protein of human papillomaviruses (HPV) binds to the upstream regulatory region (URR) of the viral genome and modulates transcription. Additionally, it seems to be a necessary component for viral DNA replication together with E1. We have developed a transgenic mouse model containing the URR region of the low-risk virus HPV11 that regulates the expression of the lacZ reporter gene. Most interestingly, in these mice, the transgene was exclusively expressed in the bulge region of the hair follicle but not in any other tissues. Further experimental data indicate that in double transgenic mice that also express the HPV11-E2 protein under the control of the Ubiquitin C-promoter, the transcription of the reporter gene is modulated. When E2 is present, the expression of the reporter gene also occurs exclusively in the bulge region of the hair follicles as it does in the single transgenic mice, but the expression of the lacZ driven by the URR is increased and the statistical spread is greater. Even if the expression of the reporter gene occurs in the hair follicles of the dorsal skin of an animal uniform, E2 obviously has the capacity for both to induce and to repress the URR activity in vivo.

Simulation of Air Travel-Related Irradiation Exposure of Cryopreserved Mouse Germplasm Samples.

Cryopreservation of genetically modified mouse lines prevents the loss of specific mutants that are of enormous scientific value for both basic and applied research. Cryopreservation of spermatozoa or preimplantation embryos enables discontinuation of breeding as well as archiving of specific lines for future studies. Regarding active inter-laboratory exchange of mutants, cryopreserved material is more advantageous to transport than live animals. However, transportation stress should not be trivialized. Security scanning of transport boxes at airports and customs, in particular, as well as additional cosmic radiation, pose a threat to undefined dosages of irradiation exposure. To simulate this, cryopreserved samples of mouse spermatozoa and preimplantation embryos were exposed to an X-ray dosage of 1 mGy in an X-ray machine. For subsequent investigation of the cell integrity of irradiated spermatozoa and embryos, spermatozoa forward motility as well as embryo developmental capacity and apoptosis values were examined and compared with nonirradiated control samples. The percentage of forward-moving spermatozoa per sample appears to be significantly reduced after irradiation exposure. The in vitro developmental capacity of preimplantation embryos as well as their relative share of apoptotic cells do not seem to be influenced by irradiation exposure. This leads to the assumption that, at least in preimplantation embryos, X-ray dosages of 1 mGy do not induce sudden severe cellular harm. Nevertheless, stochastic effects of ionizing irradiation, such as mutations, do not have a dosage threshold and always represent the potential danger of alterations to cells and cellular components, especially the DNA. This could lead to undefined mutations inducing genetic drift, in the worst case to the loss of a mutant line. We therefore strongly recommend minimizing "transportation stress," in particular by irradiation exposure, to keep its potential consequences in mind, and to standardize shipping procedures.