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Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.

The endoplasmic reticulum (ER) is a large continuous membranous organelle that plays a central role as the hub of protein and lipid synthesis while the mitochondria is the principal location for energy production. T cells are an immune subset exhibiting robust dependence on ER and mitochondrial function based on the need for protein synthesis and secretion and metabolic dexterity associated with foreign antigen recognition and cytotoxic effector response. Intimate connections exist at mitochondrial-ER contact sites (MERCs) that serve as the structural and biochemical platforms for cellular metabolic homeostasis through regulation of fission and fusion as well as glucose, Ca 2+ , and lipid exchange. Work in the tumor immunotherapy field indicates that the complex interplay of nutrient deprivation and tumor antigen stimulation in the tumor microenvironment places stress on the ER and mitochondria, causing dysfunction in organellar structure and loss of metabolic homeostasis. Here, we assess prior literature that establishes how the structural interface of these two organelles is impacted by the stress of solid tumors along with recent advances in the manipulation of organelle homeostasis at MERCs in T cells. These findings provide strong evidence for increased tumor immunity using unique therapeutic avenues that recharge cellular metabolic homeostasis in T cells.

The incidence of preterm birth in developed countries has risen in the past decades. Underlying causes for this enigmatic pregnancy complication are numerous, yet infectious agents that induce dysregualtion of immunity at the maternal-fetal interface pose one of the most probable causes of preterm birth. This paper highlights two factors regarding maternal infections that trigger unscheduled inflammatory sequences that are deleterious to the maternal-fetal balance necessary to maintain pregnancy. Firstly, we discuss the role of Toll-like receptors (TLRs) as sentinels of uterine immunity in the context of response to pathogens. We highlight the idea that particular TLR activations lead to differential immune cascades that induce preterm birth. Secondly, two alternative routes of pathogenic entry may prove to be critical for inducing preterm birth via a cytokine storm or a secondary and currently unknown cell-mediated mechanism of uterine inflammation. This paper summarizes pathways that underlie activation of adverse and diverse immune responses to foreign agents that may result in preterm birth.

BackgroundAdoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity.MethodsIn this study we investigated how tumor-specific murine CD8+ T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG.ResultsHerein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell—B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+ T cells acquired a unique proteomic signature hallmarked by an IL-2RαhighICOShighCD39low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2RαhighICOShighCD39low phenotype. CpG fostered the expansion of potent CD8+ T cells with the signature phenotype and antitumor ability via empowering a direct B–T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture.ConclusionsOur results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+ T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.

The solid tumor microenvironment is replete with factors that present a stress to infiltrating immune cells. Endoplasmic reticulum (ER) stress sensor PKR-like ER kinase (PERK) is primed to sense and respond to the burden of misfolded proteins in the ER lumen induced by cell stressors. PERK has documented roles as a master regulator of acute and chronic responses to cell stress as well as in the regulation of cell metabolism. Here, we provide an overview of the roles of PERK based on what is known and remains to be tested in immune cells in tumors and impacts on tumor control. PERK is one of several ER kinases able to preferentially induce activating transcription factor 4 (ATF4) as a response to cell stress. ATF4 orchestrates the oxidative stress response and governs amino acid metabolism. We discuss the tested role of ATF4 in tumor immunity and provide insight on the dueling protective and deleterious roles that ATF4 may play in the stress of solid tumors.

Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors and is mediated by CD8 T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.

Molecular chaperones control a multitude of cellular functions via folding chaperone-specific client proteins. CD4+FOXP3+ Tregs play key roles in maintaining peripheral tolerance, which is subject to regulation by multiple molecular switches, including mTOR and hypoxia-inducible factor. It is not clear whether GP96 (also known as GRP94), which is a master TLR and integrin chaperone, controls Treg function. Using murine genetic models, we demonstrated that GP96 is required for Treg maintenance and function, as loss of GP96 resulted in instability of the Treg lineage and impairment of suppressive functions in vivo. In the absence of GP96, Tregs were unable to maintain FOXP3 expression levels, resulting in systemic accumulation of pathogenic IFN-γ-producing and IL-17-producing T cells. We determined that GP96 serves as an essential chaperone for the cell-surface protein glycoprotein A repetitions predominant (GARP), which is a docking receptor for latent membrane-associated TGF-β (mLTGF-β). The loss of both GARP and integrins on GP96-deficient Tregs prevented expression of mLTGF-β and resulted in inefficient production of active TGF-β. Our work demonstrates that GP96 regulates multiple facets of Treg biology, thereby placing Treg stability and immunosuppressive functions strategically under the control of a major stress chaperone.

Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeutic platform to induce malignant cell death. E64FC26 is a recently identified protein disulfide isomerase (PDI) inhibitor that activates the UPR, oxidative stress, and apoptosis in tumor cells, but not normal cell types. Given that targeting cellular redox homeostasis is a strategy to augment T cell tumor control, we tested the effect of E64FC26 on healthy and oncogenic T cells. In stark contrast to the pro-UPR and pro-death effects we observed in malignant T cells, we found that E64FC26 improved viability and limited the UPR in healthy T cells. E64FC26 treatment also diminished oxidative stress and decreased global PDI expression in normal T cells. Oxidative stress and cell death are limited in memory T cells and we found that PDI inhibition promoted memory traits and reshaped T cell metabolism. Using adoptive transfer of tumor antigen-specific CD8 T cells, we demonstrate that T cells activated and expanded in the presence of E64FC26 control tumor growth better than vehicle-matched controls. Our data indicate that PDI inhibitors are a new class of drug that may dually inhibit tumor cell growth and improve T cell tumor control.

Early and late-term pregnancy maladies are thought to correlate with infection and inflammation at the maternal-fetal interface. Infectious agents may manifest systemically or through intrauterine routes, and are often present at subclinical levels. Consequently, their ability to initiate adverse pregnancy outcomes and the mechanisms that facilitate resultant pregnancy disorders remain largely unknown. A delicate juxtaposition exists at the maternal-fetal interface composed of a tightly regulated pro- and anti-inflammatory milieu that simultaneously allows placental growth and protection of the fetal allograft. Interleuikin-10 (IL-10) and Toll-like receptors (TLRs) are key components that contribute to the maintenance of equilibrium throughout pregnancy. IL-10 is a regulatory cytokine produced by the majority of cells at the maternal-fetal interface. TLRs, ubiquitous at the maternal-fetal interface, are innate immune sentinel receptors evolved to recognize pathogen-associated molecular patterns (PAMPs). The central hypothesis of this work is that IL-10 deficiency coupled with an inflammatory insult may lead to adverse pregnancy outcomes mediated by dysregulation of uterine immunity through pathogenic activation of TLRs. This work explores dysregulation of the uterine immune system in response to agonists for TLR-3, TLR-4, and TLR-9. IL-10-/- and wild-type (WT) mice are utilized in a pregnancy model to delineate the role of pathogenic TLR activation. We show that, in IL-10-/- mice, TLR-9 activation induces a unique immune cascade marked by production of mKC, neutrophil, and macrophage placental influx, and adverse pregnancy outcomes mediated by a TNF-a-macrophage axis. In contrast, we demonstrate that TLR-3-mediated immune dysregulation is not dependent on the availability of IL-10. Rather, in response to TLR-3 activation, IL-10 deficiency leads to an alternative program of cellular response as fetal resorption in WT mice is mediated by a uNK-TNF-a-axis, while IL-10-/- mice experience fetal demise as a result of a T-cell-TNF-a axis. Finally, we show that intrauterine administration of TLR-4 agonist causes detrimental effects to the ipsilateral versus contralateral horn marked by uNK cell-mediated placental pathology in the ipsilateral horn only. Taken together, these findings elucidate novel cellular mechanisms at the maternal-fetal interface that induces adverse pregnancy outcomes in response to bacterial and viral mimics.