The role of the immune system in anti-tumor immunity cannot be overstated, as it holds the potential to promote tumor eradication or prevent tumor cell escape. Cytokines are critical to influencing the immune responses and interactions with non-immune cells. Recently, the IL-12 and IL-6 family of cytokines have accumulated newly defined members each with specific immune functions related to various cancers and tumorigenesis. There is a need to better understand how cytokines like IL-27, IL-30, and IL-35 interact with one another, and how a developing tumor can exploit these interactions to enhance immune suppression. Current cytokine-based immunotherapies are associated with cytotoxic side effects which limits the success of treatment. In addition to this toxicity, understanding the complex interactions between immune and cancer cells may be one of the greatest challenges to developing a successful immunotherapy. In this review, we bring forth IL-27, IL-30, and IL-35, “sister cytokines,” along with more recent additions to the IL-12 family, which serve distinct purposes despite sharing structural similarities. We highlight how these cytokines function in the tumor microenvironment by examining their direct effects on cancer cells as well their indirect actions via regulatory functions of immune cells that act to either instigate or inhibit tumor progression. Understanding the context dependent immunomodulatory outcomes of these sister cytokines, as well as their regulation within the tumor microenvironment, may shed light onto novel cancer therapeutic treatments or targets.

CD8+ cytotoxic T cell (CTL) responses are necessary for the lysis of virally infected cells and control of infection. CTLs are activated when their TCRs bind a major histocompatibility complex (MHC)-I/peptide complex on the surface of antigen presenting cells such as macrophages (MΦ). It is now apparent that MΦ display remarkable plasticity in response to environmental signals to polarize into classically activated M(LPS + IFN-γ) or alternatively activated M(IL-4). However, little is known about how MΦ activation status influences their antigen presentation function to CD8+ T cell in models of virus infection. Consequently, we tested how polarization of spleen-derived (Sp)-MΦ impacts direct presentation of viral antigens to influence effector and proliferative CD8+ T-cell responses. We show that M(IL-4) Sp-MΦ retain MHC-I surface expression and the ability to stimulate IFN-γ production by CTL following peptide stimulation and lymphocytic choriomeningitis virus infection to levels similar to M0 and M(LPS + IFN-γ) MΦ. However, memory CD8+ T cells cultured in the presence of M(IL-4) MΦ underwent significantly reduced proliferation and produced similar IFN-γ levels as coculturing with M0 or M(LPS + IFN-γ) cells. Thus, these results show a novel ability of polarized MΦ to regulate CD8+ T-cell proliferation and effector functions during virus infection.

Nearly a decade ago, an endoplasmic reticulum (ER) adaptor protein called stimulator of interferon genes (STING) was found to be critical in the induction of type I IFN production in response to DNA virus infection. STING functions by sensing cytoplasmic DNA and activates key transcription factors, including IFN regulatory factor (IRF)-3 and IRF7, to initiate type I IFN expression. Type I IFNs are vital in immunity against viral infections and can influence cancer cell proliferation, migration, and apoptosis. Several studies have shown that STING activation results in potent antitumor activity by generating strong tumor-specific cytotoxic T-cell responses. Moreover, compared with wild-type, STING-knockout mice show greater susceptibility to viral infections. In this review, we discuss the importance of STING signaling during the induction of immune responses, especially those associated with type I IFN in viral infections and tumor immunity. Furthermore, we highlight recent data that unravel how the STING signaling pathway can be negatively regulated.

Granulocyte/macrophage colony-stimulating factor (GM-CSF) and macrophage CSF (M-CSF) modulate differentiation and immune functions of macrophages (MF). Our aim was to evaluate how different MF differentiation conditions influence the MF response to virus infection. To address this, we differentiated bone marrow-derived MF in either GM-CSF or M-CSF and measured the cytokine responses to two different strains of lymphocytic choriomeningitis virus (LCMV) (clone 13; Cl13 or Armstrong; ARM). GM-CSF MF infected with either LCMV-ARM or -Cl13 produced more IL-6 than M-CSF MF, whereas M-CSF MF generated more IL-10 than GM-CSF MF. Interestingly, in M-CSF MF, LCMV-ARM induced more IL-10 production than Cl13. However, we could not detect any IL-12p70 or IL-23 after infection from either cell types. We also observed that GM-CSF MF was more efficient than M-CSF MF in supporting antigen-specific CD8 + T cell proliferation. Taken together, our data demonstrate that GM-CSF and M-CSF MF differ in how they respond to viral infection by their production of different cytokines, and their support for CD8 + T cell proliferation.

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