Cholesterol negatively regulates IL-9–producing CD8+ T cell differentiation and antitumor activity

Abstract

CD8+ T cells can be polarized into IL-9–secreting (Tc9) cells. Ma et al. show that Tc9 cell differentiation is associated with a low cholesterol reprogramming profile, and manipulating cholesterol content in polarizing Tc9 cells significantly affects Tc9 differentiation and antitumor response.

Less cholesterol means better tumor killing for cytotoxic T9 cells

“…Type 9 cells have been shown to persist long term in vivo after transfer in multiple studies (Lu et al, 2012, 2014; Ramadan et al, 2017). Ma et al (2018) show here that Tc9 cells from Pmel-1 mice, a transgenic strain that carries a rearranged T cell receptor specific for pmel-17, an orthologue of the melanocyte differentiation antigen gp100, which is overexpressed in many human melanomas, persist longer than Tc1 cells when adoptively transferred into MC38-gp100 tumor bearing mice. Treatment of Tc9 cells with β-CD before adoptive transfer increased their persistence in vivo, whereas treatment with cholesterol decreased their persistence compared with untreated Tc9 cells by decreasing and increasing apoptosis, respectively.…”

“…In T cells, cholesterol can influence TCR signaling, immunological synapse formation, and cytokine secretion, all of which can influence antitumor activity (Wang et al, 2016; Yang et al, 2016). To identify cholesterol as a negative regulator of Tc9 differentiation, Ma et al (2018) first used Ingenuity Pathway Analysis comparing microarrays from murine cytotoxic CD8 T cells differentiated under type 1 (IL-2 and IL-12) and type 9 (TGF-β and IL-4) cytokine conditions. They found that Tc9 cells have lower basal expression of cholesterol synthesis genes, such as Hmgcr and Sqle , and high expression of cholesterol efflux genes, such as Abca1 and Abcg1 , than Tc1 cells.…”

“…One of the more interesting data Ma et al (2018) received from their microarray study was the increase in Il1rl1 expression. Il1rl1 encodes for the protein ST2, also known as the IL-33 receptor.…”

“…It would be exciting to see if removing cholesterol during in vitro differentiation or with systemic administration of statins along with addition of IL-33 could further increase the antitumor potential of these T cells. In addition, IL-9 seems to be a driver of antitumor activity of these cells, as loss of IL-9 abrogated the effects of β-CD and IL-33 (Ramadan et al, 2017; Ma et al, 2018). What role IL-9 has in promoting antitumor activity has yet to be elucidated.…”

“…There are important clinical implications on modulating cholesterol during T cell culture for adoptive transfer. Although over 70% of American adults are at least overweight and almost 38% are obese (Fryar et al, 2016), treatment of overweight or obese patients with adoptively transferred Tc9 cells differentiated with minimal cholesterol may not be affected, as suggested by the experiments by Ma et al (2018) that show that wild-type Tc9 cells adoptively transferred into Apoe −/− hosts have similar antitumor activity as when transferred into wild-type hosts. However, an important caveat of these experiments is that the adoptively transferred T cells were specific for the tumor antigen.…”