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The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.

Preclinical mouse solid tumor models are widely used to evaluate efficacy of novel cancer therapeutics. Recent reports have highlighted the need for utilizing orthotopic implantation to represent clinical disease more accurately, however the deep tissue location of these tumors makes longitudinal assessment challenging without the use of imaging techniques. The purpose of this study was to evaluate the performance of a new multi-modality high-throughput in vivo imaging system that combines bioluminescence imaging (BLI) with robotic, hands-free ultrasound (US) for evaluating orthotopic mouse models. Long utilized in cancer research as independent modalities, we hypothesized that the combination of BLI and US would offer complementary advantages of detection sensitivity and quantification accuracy, while mitigating individual technological weaknesses. Bioluminescent pancreatic tumor cells were injected into the pancreas tail of C57BL/6 mice and imaged weekly with the combination system and magnetic resonance imaging (MRI) to serve as a gold standard. BLI photon flux was quantified to assess tumor activity and distribution, and US and MRI datasets were manually segmented for gross tumor volume. Robotic US and MRI demonstrated a strong agreement (R 2  = 0.94) for tumor volume measurement. BLI showed a weak overall agreement with MRI (R 2  = 0.21), however, it offered the greatest sensitivity to detecting the presence of tumors. We conclude that combining BLI with robotic US offers an efficient screening tool for orthotopic tumor models.

Cytokines that stimulate T cell proliferation, such as interleukin (IL)-15, have been explored as a means of boosting the antitumor activity of chimeric antigen receptor (CAR) T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL-23 is a two-subunit cytokine known to promote proliferation of memory T cells and T helper type 17 cells. We found that, upon T cell antigen receptor (TCR) stimulation, T cells upregulated the IL-23 receptor and the IL-23α p19 subunit, but not the p40 subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells) and obtained selective proliferative activity in activated T cells via autocrine IL-23 signaling. In comparison to CAR T cells, p40-Td CAR T cells showed improved antitumor capacity in vitro, with increased granzyme B and decreased PD-1 expression. In two xenograft and two syngeneic solid tumor mouse models, p40-Td CAR T cells showed superior efficacy in comparison to CAR T cells and attenuated side effects in comparison to CAR T cells expressing IL-18 or IL-15. The efficacy of chimeric antigen receptor (CAR) T cells in solid tumor models is enhanced by interleukin-23 engineering.

Pancreatic cancer is an aggressive malignancy, often diagnosed at metastatic stages. Several studies have implicated systemic factors, such as extracellular vesicle release and myeloid cell expansion, in the establishment of pre-metastatic niches in cancer. The Rab27a GTPase is overexpressed in advanced cancers, can regulate vesicle trafficking, and has been previously linked to non-cell autonomous control of tumor growth and metastasis, however, the role of Rab27a itself in the metastatic propensity of pancreatic cancer is not well understood. Here, we have established a model to study how Rab27a directs formation of the pre-metastatic niche. Loss of Rab27a in pancreatic cancer cells did not decrease tumor growth in vivo , but resulted in altered systemic myeloid cell expansion, both in the primary tumors and at the distant organ sites. In metastasis assays, loss of Rab27a expression in tumor cells injected into circulation compromised efficient outgrowth of metastatic lesions. However, Rab27a knockdown cells had an unexpected advantage at initial steps of metastatic seeding, suggesting that Rab27a may alter cell-autonomous invasive properties of the tumor cells. Gene expression analysis of gene expression revealed that downregulation of Rab27a increased expression of genes involved in epithelial-to-mesenchymal transition pathways, consistent with our findings that primary tumors arising from Rab27a knockdown cells were more invasive. Overall, these data reveal that Rab27a can play divergent roles in regulating pro-metastatic propensity of pancreatic cancer cells: by generating pro-metastatic environment at the distant organ sites, and by suppressing invasive properties of the cancer cells.

B cells can act as potent suppressors of anti-tumor T cell immunity, presenting a mechanism of resistance to immunotherapy. In pancreatic ductal adenocarcinoma, B cells can display a T cell-suppressive or regulatory phenotype centered on the expression of the cytokine Interleukin 35 (IL-35). While B cell-mediated immunosuppression presents a barrier to anti-tumorigenic T cell function, it is not clear how regulatory B cell function could be targeted, and the signals that promote this suppressive phenotype in B cells are not well understood. Here we use a novel IL-35 reporter model to understand which signaling pathways are important for immunosuppressive properties in B cells. In vitro analysis of IL-35 reporter B cells revealed a synergy between the BCR and TLR4 signaling pathways is sufficient to induce IL-35 expression. However, in vivo , B cell receptor activation, as opposed to MyD88 signaling in B cells, is central to B cell-mediated suppression and promotion of pancreatic cancer growth. Further analysis identified protein kinase D2 (PKD2) as being a key downstream regulator of IL-35 expression in B cells. Regulatory B cells with an inactivating mutation in PKD2 failed to produce IL-35 or fully suppress effector T cell function in vitro . Furthermore, inhibition of PKD in B cells decreased tumor growth and promoted effector T cell function upon adoptive transfer into B cell-deficient mice. Collectively, these data provide insight into how regulatory B cell function is promoted in pancreatic cancer and identify potential therapeutic targets to restrain this function.

Key Points RAS is a GTPase that is frequently mutated in cancer and that affects a variety of cancer-driving processes. Unique properties of RAS isoforms, and of particular activating mutations, may distinctly affect the process of neoplastic conversion in different tissues. RAS drives cellular proliferation by providing both cell-autonomous and non-cell-autonomous cues, which ultimately converge in the transformed cells to promote pro-growth and to inhibit anti-growth signals. RAS-mediated proliferative overdrive may induce replicative stress and activation of DNA damage responses. The suppression of a cell death response by oncogenic RAS is a consequence of a perturbation of homeostatic balance between pro-apoptotic and anti-apoptotic signals. To keep up with the high energy needs of growing cells, the survival of RAS-transformed cells is further aided by metabolic reprogramming towards glycolysis that is mediated by MAPK- and PI3K-dependent regulation of hypoxia-inducible factor 1α (HIF1α). Oncogenic RAS modulates the tumour microenvironment by promoting pro-angiogenic mechanisms and by altering host-mediated immune responses. Transformation by RAS can also promote changes in motility and cellular adhesion, leading to the acquisition of invasive and metastatic properties of cancer cells. Breakthroughs in real-time imaging, computational approaches, high-throughput screening and genetically engineered mouse modelling promise to advance our capacity to integrate the complexity of RAS signalling pathways with the context specificity of their oncogenic activities, undoubtedly aiding the implementation of successful remedial strategies in the clinic. The RAS oncogenes have far-reaching effects when they are oncogenically mutated. This Review discusses our current knowledge about the cell-autonomous and non-cell-autonomous effects of oncogenic RAS and how different RAS isoforms and substitutions seem to have different effects. RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis.

An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers 1 – 3 . Agonists of the stimulator of interferon g enes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression 4 . Although these agonists hold promise as potential cancer therapies 5 , tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear 5 – 7 . Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35 + regulatory B cells in pancreatic cancer. Mechanistically, cGAMP drives expression of IL-35 by B cells in an IRF3-dependent but type I interferon-independent manner. In several preclinical cancer models, the loss of STING signalling in B cells increases tumour control. Furthermore, anti-IL-35 blockade or genetic ablation of IL-35 in B cells also reduces tumour growth. Unexpectedly, the STING–IL-35 axis in B cells reduces proliferation of natural killer (NK) cells and attenuates the NK-driven anti-tumour response. These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours. Systemic treatment of pancreatic cancer with STING agonist stimulates regulatory B cells to express immunosuppressive cytokine IL-35, which weakens the anti-tumour function of natural killer cells.

Almost 1 million people in the United States suffer from multiple sclerosis (MS). Current therapies suppress protective immunity and are non-curative. Antigen-specific therapies can selectively suppress autoreactive cells, preserving protective immunity. B cell dysregulation, a major driver of MS, remains largely untargeted for antigen-specific tolerance. We hypothesize that targeting B cells with antigen-loaded microparticles will enhance therapeutic efficacy. Here, we demonstrate that antigen-loaded acetalated dextran microparticles (AMP) surface-associate with B cells and enhance IL-10 secretion and MHCII expression, promoting tolerogenic antigen presentation. Leveraging this property, we developed a therapy using myelin oligodendrocyte (MOG ) peptide-loaded AMPs associated with B cells (MOG-AMP-B). Administering MOG-AMP-Bs in a late therapeutic model of multiple sclerosis resulted in unprecedented recovery, reducing central nervous system (CNS) inflammation, downregulating activated dendritic cells and macrophages, and increasing regulatory T- and B cells. MOG-AMP-Bs did not reduce the ability of animals to respond to a viral infection, representing a highly effective antigen-specific therapy for restoring immune balance in autoimmunity.

Cytokines that stimulate T cell proliferation, such as IL15, have been explored as a means of boosting the anti-tumor activity of chimeric antigen receptor (CAR)-T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL23 is a two-subunit cytokine known to promote proliferation of memory T cells and Th17 cells. We found that, upon T cell receptor (TCR) stimulation, T cells upregulate the IL23 receptor and the IL23α p19, but not the p40, subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells), and obtained a selective proliferative activity in activated T cells via autocrine IL23 signaling. Compared to CAR-T cells, p40-Td CAR-T cells showed improved anti-tumor capacity in vitro, with increased granzyme B and decreased PD-1 expression. In two xenograft and two syngeneic solid tumor mouse models, p40-Td CAR-T cells showed superior efficacy compared with CAR-T cells and attenuated side effects compared with CAR-T cells expressing IL18 or IL15.