The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.
Tumor-specific CD8+ T cells are critical components of antitumor immunity; however, factors that modulate their phenotype and function have not been completely elucidated. Cytokines IL-12 and IL-27 have recognized roles in promoting CD8+ T cells’ effector function and mediated antitumor responses. Tumor-specific CD8+ tumor-infiltrating lymphocytes (TILs) can be identified based on surface expression of CD39, whereas bystander CD8+ TILs do not express this enzyme. It is currently unclear how and why tumor-specific CD8+ T cells uniquely express CD39. Given the important roles of IL-12 and IL-27 in promoting CD8+ T cell functionality, we investigated whether these cytokines could modulate CD39 expression on these cells. Using in vitro stimulation assays, we identified that murine splenic CD8+ T cells differentially upregulate CD39 in the presence of IL-12 and IL-27. Subsequently, we assessed the exhaustion profile of IL-12– and IL-27–induced CD39+CD8+ T cells. Despite the greatest frequency of exhausted CD39+CD8+ T cells after activation with IL-12, as demonstrated by the coexpression of TIM-3+PD-1+LAG-3+ and reduced degranulation capacity, these cells retained the ability to produce IFN-γ. IL-27–induced CD39+CD8+ T cells expressed PD-1 but did not exhibit a terminally exhausted phenotype. IL-27 was able to attenuate IL-12–mediated inhibitory receptor expression on CD39+CD8+ T cells but did not rescue degranulation ability. Using an immunogenic neuro-2a mouse model, inhibiting IL-12 activity reduced CD39+CD8+ TIL frequency compared with controls without changing the overall CD8+ TIL frequency. These results provide insight into immune regulators of CD39 expression on CD8+ T cells and further highlight the differential impact of CD39-inducing factors on the phenotype and effector functions of CD8+ T cells.
Background Tumor-specific CD8 + T-cells play a critical role in tumor control, as demonstrated by the success of immune checkpoint inhibitors and adoptive cell therapy. Studies of mice and human tumor-infiltrating lymphocytes (TILs) demonstrate that tumor-specific CD8 + TILs can be defined by CD39 expression on their surface. CD39 is commonly considered an immunosuppressive enzyme, as it depletes ATP. However, CD39 is also associated with mitigating activation-induced cell death and mediating leukocyte trafficking. It is, however, unclear whether CD39 expression on tumor-specific T-cells can be regulated by putative anti-tumor factors such as proinflammatory cytokines similar to the phenotype and antitumor properties of CD8 + TILs. IL-12 and IL-27 have established roles in promoting effector T-cell differentiation, expansion, and cytotoxic activity. Both cytokines are implicated in the upregulation of CD39 by T regulatory cells, suggesting they may regulate CD39 expression in other cell types, including tumor-specific CD8 + T-cells. We hypothesize that IL-12 and IL-27 induce CD39 upregulation on CD8 + T-cells, modulating their anti-tumor properties. Methods An engineered immunogenic, syngeneic neuroblastoma (neuro-2a) mouse model was used for in vitro and in vivo experiments. CD8 + T-cells or bulk splenocytes isolated from naïve or neuro-2a vaccinated mice were stimulated in vitro using anti-CD3/CD28 Dynabeads and IL-2 ± IL-12 or IL-27. Flow cytometry was used to determine the phenotype of CD8 + T-cells and assess effector activity. Additionally, we inhibited IL-12 activity in vivo to study the effect on CD8 + TIL expression of CD39. An isotype control antibody was administered to a separate group to act as a control. Results Our in vitro results demonstrate that CD8 + T-cells stimulated in the presence of IL-12 or IL-27 had higher expression of CD39 compared to stimulated controls. In addition, we found a higher frequency of CD39 + CD8 + T-cells expressing IFNg and CD107a than CD39counterparts. Finally, blocking IL-12 activity in vivo reduced CD39 + CD8 + TIL frequency compared to the isotype control group. Conclusions Our results establish that IL-12 and IL-27 induce CD39 expression on CD8 + T-cells and blocking IL-12 reduced CD39 + CD8 + TIL frequency. Furthermore, CD39 expression is associated with improved effector CD8 + T-cell function. Future experiments will assess the functionality of CD39 + CD8 + T-cells using ex vivo cytotoxicity assays. Data generated in this study will provide novel information on the mechanism of CD39 induction and its effect on CD8 + T-cell function, which can be exploited to improve future cancer therapies.
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