IL-12 and IL-27 Promote CD39 Expression on CD8+ T Cells and Differentially Regulate the CD39+CD8+ T Cell Phenotype.

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.

Inducing mismatch repair deficiency sensitizes immune-cold neuroblastoma to anti-CTLA4 and generates broad anti-tumor immune memory.

Immune checkpoint blockade can induce potent and durable responses in patients with highly immunogenic mismatch repair-deficient tumors; however, these drugs are ineffective against immune-cold neuroblastoma tumors. To establish a role for a T cell-based therapy against neuroblastoma, we show that T cell and memory T cell-dependent gene expression are associated with improved survival in high-risk neuroblastoma patients. To stimulate anti-tumor immunity and reproduce this immune phenotype in neuroblastoma tumors, we used CRISPR-Cas9 to knockout MLH1-a crucial molecule in the DNA mismatch repair pathway-to induce mismatch repair deficiency in a poorly immunogenic murine neuroblastoma model. Induced mismatch repair deficiency increased the expression of proinflammatory genes and stimulated T cell infiltration into neuroblastoma tumors. In contrast to adult cancers with induced mismatch repair deficiency, neuroblastoma tumors remained unresponsive to anti-PD1 treatment. However, anti-CTLA4 therapy was highly effective against these tumors. Anti-CTLA4 therapy promoted immune memory and T cell epitope spreading in cured animals. Mechanistically, the effect of anti-CTLA4 therapy against neuroblastoma tumors with induced mismatch repair deficiency is CD4+ T cell dependent, as depletion of these cells abolished the effect. Therefore, a therapeutic strategy involving mismatch repair deficiency-based T cell infiltration of neuroblastoma tumors combined with anti-CTLA4 can serve as a novel T cell-based treatment strategy for neuroblastoma.

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy.

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.