A proposed paper by Hope et al. (2023) evaluated the role of PSGL-1 (P-selectin glycoprotein-1) concerning the growth or suppression of cancer cells in mice and humans. The authors show that PSGL-1 requires co-ligation with TCR to attenuate CD8+ T-cell activation and consequently induce depletion. By depletion, Hope et al. mean the partial or complete loss of immune functions of CD8+ T cells, and thus the inability to respond to and effectively suppress cancer cells.
Based on the information obtained, the authors conclude that PSGL-1 deficiency positively affects the immune system, as it predicts an increase in the number of CD8+ T-cell progenitors. In other words, since the role of CD8+ T cells is critical to the organization and efficient functioning of the immune system, their numbers matter. The converse is also true: pharmacologic inhibition of PSGL-1 can block the receptor pathway and, consequently, deplete T cells.
The current study has several important implications for the scientific and clinical community regarding practical value. First, it creates opportunities for developing novel immunotherapeutic strategies to block PSGL-1. Second, a more detailed study of PSGL-1 holds great promise for understanding the nature of immune cell depletion.
However, it is worth noting that this study posed risks to the reliability of its conclusions. In particular, it should not rule out the possibility that the described association between PSGL-1 and CD8+ T cells may be mediated by additional factors not included in the study. It is possible that PSGL-1 is not the main factor of T-cell depletion but only participates in this process. At the same time, it cannot be excluded that PSGL-1 blockade is strictly beneficial; in other words, it may entail adverse side effects. It follows that additional studies are needed to confirm the findings and prove the safety of the PSGL blockade.
There are several potential directions for the development of the described study. First, it may be possible to investigate in more detail how PSGL-1 blockade affects other immune cell types. Second, it would be worthwhile to determine the clinical consequences of PSGL-1 blockade.
Reference
Hope, J. L., Otero, D. C., Bae, E. A., Stairiker, C. J., Palete, A. B., Faso, H. A., & Bradley, L. M. (2023). PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion. Cell Reports, 42(5), 1-27.