Sox matters!

Our research focus on molecular switches, which control the activity of immune cells in particular T lymphocytes. This cell type can cause harm to the bodys own constituents and thus mediate autoimmune pathology. However, T lymphocytes protect us against the development of cancer by killing tumor cells. Of note, prevalence and prognosis of these immune-related diseases differ between male and female: while female are more susceptible to autoimmune disorders, their risk to develop tumors is reduced. Nevertheless, immune checkpoint blockade therapy (ICT), which aims to activate immune cells to fight tumor cells, is more effective in male cancer patients. Interestingly, the X chromosome, of which male have one and female two, is highly enriched in immune-related genes. Therefore, variable expression of x-chromosomal genes, is likely to contribute to sex disparity seen in cancer and autoimmunity. In the current research proposal, we will analyze a member of the Sox family that is encoded on the X chromosome. So far nothing is known about its role in lymphocytes. Originally, we identified this gene as a potential immune-modulator in a screen that aimed to discover genes regulating T lymphocyte activity in pregnant women. Indeed, the activity of T lymphocytes towards the fetus, which is due to the genes of the father half-foreign, needs to be suppressed. In our proposed study, we will address whether Sox is involved in sex dimorphism of anti-cancer immunity. It will be analyzed if manipulation of Sox function impacts on tumor development and thus, presents a potential therapeutic target. Furthermore, we will investigate whether it s expression correlates with the functional status of T lymphocytes and whether it has the potential to function as a biomarker to help select male and female patients for ICT or alternative treatments in the future.

In the current research proposal, we analyzed the x-chromosome-encoded transcription factor Sox3, whose role in T lymphocytes has not been previously addressed. We originally identified this gene as a potential immune-modulator in a screen aimed at discovering genes that regulate T lymphocyte activity in pregnant women. We hypothesized that Sox3 is involved in the sex dimorphism of anti-cancer immunity and represents a potential new target to improve T cell-mediated immunotherapy. However, our results obtained with crispr/cas-based approaches suggest that Sox3 is dispensable for T lymphocyte activation and function in vitro as well as in vivo (after adoptive transfer using preclinical models). Furthermore, we observed only very low levels of Sox3 mRNA expression in T lymphocytes, which did not correlate with the activation or differentiation status of the T cell. Consistent with this, Sox3 transcripts were not detected in tumor-infiltrating T lymphocytes isolated from biopsies of NSCLC patients (analyzed by single-cell RNA sequencing). Thus, our results unfortunately contradict our hypothesis that Sox3 acts as a novel immune checkpoint of T lymphocyte activity.