Implications For Cancer Immunotherapy Research Articles

Discovery of a proteolysis targeting chimera (PROTAC) as a potent regulator of FOXP3

Regulatory T (Treg) cells play a central role in immune homeostasis. Forkhead box P3 (Foxp3), a hallmark molecule in Treg cells, is a vital transcription factor for their development and function. Studies have shown that degradation of the Foxp3 could provide therapeutic benefits in achieving effective anti-tumor immunity. In this study, we designed three PROTAC molecules, P60-L1-VHL, P60-L2-VHL, and P60-L3-VHL, based on a 15-mer peptide inhibitor of Foxp3 (P60), and explored their potential in regulating Foxp3 expression and function. Our data show that, among these molecules, P60-L3-VHL can inhibit the expression and nuclear localization of Foxp3 in HEK 293 T and HeLa cells, respectively. Meanwhile, use of proteasome inhibitor in P60-L3-VHL treated cells revealed an increased Foxp3 expression, indicating that P60-L3-VHL mediates the inhibition of Foxp3 through its degradation in the proteasome pathway. We further substantiate that P60-L3-VHL reduces the differentiation and Foxp3 expression in the in-vitro activated Treg cells. Overall, our findings suggest that P60-L3-VHL inhibits the differentiation of Treg cells by degrading the Foxp3, which may have potential implications in cancer immunotherapy.

Epigenetic regulation of HERVs: Implications for cancer immunotherapy.

Human endogenous retroviruses (HERVs), integrated into the human genome during primate evolution, constitute approximately 8% of the human genome. Although most HERVs are non-protein-coding owing to mutations, insertions, deletions, and truncations, recent research has revealed their diverse roles in biological processes, including disease pathogenesis. Although many HERVs remain inactive, they have been implicated in various diseases, particularly cancer, prompting an increased interest in harnessing HERVs for therapeutic purposes. This review explores the recent advancements in our understanding of the biological roles of HERVs, emphasizing their clinical relevance in cancer treatment. Here, we discuss how the detection of transposable elements (TEs), including HERVs, by the immune system triggers innate immune responses in human cancers. Additionally, we outline recent progress in elucidating the implications of HERV activation in cancer and how targeting HERVs holds promise for anti-cancer treatments by modulating epigenetic plasticity and disrupting cancer initiation and progression.

Dendritic cell subsets and implications for cancer immunotherapy.

Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.

Programmed Death Ligand 1 Regulatory Crosstalk with Ubiquitination and Deubiquitination: Implications in Cancer Immunotherapy.

Programmed death ligand 1 (PD-L1) plays a pivotal role in cancer immune evasion and is a critical target for cancer immunotherapy. This review focuses on the regulation of PD-L1 through the dynamic processes of ubiquitination and deubiquitination, which are crucial for its stability and function. Here, we explored the intricate mechanisms involving various E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) that modulate PD-L1 expression in cancer cells. Specific ligases are discussed in detail, highlighting their roles in tagging PD-L1 for degradation. Furthermore, we discuss the actions of DUBs that stabilize PD-L1 by removing ubiquitin chains. The interplay of these enzymes not only dictates PD-L1 levels but also influences cancer progression and patient response to immunotherapies. Furthermore, we discuss the therapeutic implications of targeting these regulatory pathways and propose novel strategies to enhance the efficacy of PD-L1/PD-1-based therapies. Our review underscores the complexity of PD-L1 regulation and its significant impact on the tumor microenvironment and immunotherapy outcomes.

The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells

CD8+ T cells play an important role in anti-tumor immunity. Better understanding of their regulation could advance cancer immunotherapies. Here we identify, via stepwise CRISPR-based screening, that CUL5 is a negative regulator of the core signaling pathways of CD8+ T cells. Knocking out CUL5 in mouse CD8+ T cells significantly improves their tumor growth inhibiting ability, with significant proteomic alterations that broadly enhance TCR and cytokine signaling and their effector functions. Chemical inhibition of neddylation required by CUL5 activation, also enhances CD8 effector activities with CUL5 validated as a major target. Mechanistically, CUL5, which is upregulated by TCR stimulation, interacts with the SOCS-box-containing protein PCMTD2 and inhibits TCR and IL2 signaling. Additionally, CTLA4 is markedly upregulated by CUL5 knockout, and its inactivation further enhances the anti-tumor effect of CUL5 KO. These results together reveal a negative regulatory mechanism for CD8+ T cells and have strong translational implications in cancer immunotherapy.

PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αβ T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

Function of Steroid Receptor Coactivators in T Cells and Cancers: Implications for Cancer Immunotherapy.

Steroid receptor coactivator (SRC) family members (SRC1, SRC2 and SRC3) are transcriptional co-regulators. SRCs orchestrate gene transcription by inducing transactivation of nuclear receptors and other transcription factors. Overexpression of SRCs is widely implicated in a range of cancers, especially hormone-related cancers. As coactivators, SRCs regulate multiple metabolic pathways involved in tumor growth, invasion, metastasis, and chemo-resistance. Emerging evidence in recent years suggest that SRCs also regulate maturation, differentiation, and cytotoxicity of T cells by controlling metabolic activities. In this review, we summarize the current understanding of the function of SRCs in T cells as well as cancer cells. Importantly, the controversies of targeting SRCs for cancer immunotherapy as well as possible reconciliation strategies are also discussed.

Unraveling the genetic associations between PD-1/PD-L1 and 13 circulating biomarkers linked to physiological and pathological processes.

Evidence of the genetic interconnectedness between PD-1/PD-L1 and circulating biomarkers related to physiological and pathological processes is largely unclear. Understanding these genetic links is crucial for gaining insights into the underlying mechanisms and potential implications in cancer immunotherapy. To shed light on potential roles of 90 circulating biomarkers in PD-1/PD-L1, we conducted a comprehensive Mendelian randomization (MR) analysis, leveraging genetic data from large-scale genome-wide association studies. Our results revealed negative associations between EN-RAGE and TRAIL-R2 with PD-1 levels. Additionally, we observed that PD-1 levels were positively associated with TRAIL, VEGF, and ANPEP, indicating their potential role in PD-1 upregulation. Furthermore, our analysis revealed causal associations between several circulating proteins and PD-L1 levels. Thrombomodulin, PSGL-1, TNFSF14, renin, follistatin, β-NGF, KLK6, and MMP-7 demonstrated significant effects on PD-L1 regulation, suggesting their potential inhibitory role in immune checkpoint regulation. Eventually, we confirmed the potential roles of key genes involved in above circulating proteins in influencing the response to immunotherapy. Our findings provide valuable evidence of the genetic interconnectedness between PD-1/PD-L1 and circulating proteins related to physiological and pathological processes, shedding light on their potential roles in disease progression and therapeutic interventions.

IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy.

Interferon-gamma (IFN-γ), the sole member of the type-II interferon family, is well known to protect the host from infectious diseases as well as mount anti-tumor responses. The amounts of IFN-γ in the tumor microenvironment determine the host responses against tumors; however, several tumors employ evasive strategies by responding to low IFN-γ signaling. In this study, the response of various tumor cell lines to IFN-γ was studied in vitro. IFN-γ-activation increases glycolytic flux and reduces mitochondrial function in a nitric oxide (NO)- and reactive oxygen species (ROS)-dependent manner in the H6 hepatoma tumor cell line. The higher glycolysis further fueled NO and ROS production, indicating a reciprocal regulation. These processes are accompanied by Hypoxia inducing factor (HIF)-1α stabilization and HIF-1α-dependent augmentation of the glycolytic flux. The IFN-γ enhancement of lactate production also occurred in other NO-producing cell lines: RAW 264.7 monocyte/macrophage and Renca renal adenocarcinoma. However, two other tumor cell lines, CT26 colon carcinoma and B16F10 melanoma, did not produce NO and lactate upon IFN-γ-activation. HIF-1α stabilization upon IFN-γ-activation led to lower cell growth of B16F10 but not CT26 cells. Importantly, the IFN-γ-activation of both CT26 and B16F10 cells demonstrated significant cellular growth reduction upon metabolic rewiring by exogenous administration of potassium lactate. Clinical studies have shown the crucial roles of IFN-γ for successful cancer immunotherapies involving checkpoint inhibitors and chimeric antigen receptor T cells. The positive implications of this study on the metabolic modulation of IFN-γ activation on heterogeneous tumor cells are discussed.

2O PD-1 defines a distinct, functional, tissue-adapted state in V-delta-1+ T cells with implications for cancer immunotherapy

2O PD-1 defines a distinct, functional, tissue-adapted state in V-delta-1+ T cells with implications for cancer immunotherapy

Regulation of the tumor immune microenvironment by the Hippo Pathway: Implications for cancer immunotherapy.

The tumor immune microenvironment (TIME) is a dynamic and complex ecosystem consisting of immune cells, stromal cells, and tumor cells. It plays a crucial role in shaping cancer progression and treatment outcomes. Notably, tumor-associated immune cells are key regulators within the TIME, influencing immune responses and therapeutic efficacy. The Hippo pathway is a critical signaling pathway involved in the TIME and cancer progression. In this review, we provide an overview of the Hippo pathway's role in the TIME, focusing on its interactions with immune cells and their implications in cancer biology and therapy. Specifically, we discuss the involvement of the Hippo pathway in regulating T-cell function, macrophage polarization, B-cell differentiation, MDSC activity, and dendritic cell-mediated immune responses. Furthermore, we explore its influence on PD-L1 expression in lymphocytes and its potential as a therapeutic target. While recent progress has been made in understanding the Hippo pathway's molecular mechanisms, challenges remain in deciphering its context-dependent effects in different cancers and identifying predictive biomarkers for targeted therapies. By elucidating the intricate crosstalk between the Hippo pathway and the TME, we aim to contribute to the development of innovative strategies for cancer treatment.

Biology of GD2 ganglioside: implications for cancer immunotherapy.

Part of the broader glycosphingolipid family, gangliosides are composed of a ceramide bound to a sialic acid-containing glycan chain, and locate at the plasma membrane. Gangliosides are produced through sequential steps of glycosylation and sialylation. This diversity of composition is reflected in differences in expression patterns and functions of the various gangliosides. Ganglioside GD2 designates different subspecies following a basic structure containing three carbohydrate residues and two sialic acids. GD2 expression, usually restrained to limited tissues, is frequently altered in various neuroectoderm-derived cancers. While GD2 is of evident interest, its glycolipid nature has rendered research challenging. Physiological GD2 expression has been linked to developmental processes. Passing this stage, varying levels of GD2, physiologically expressed mainly in the central nervous system, affect composition and formation of membrane microdomains involved in surface receptor signaling. Overexpressed in cancer, GD2 has been shown to enhance cell survival and invasion. Furthermore, binding of antibodies leads to immune-independent cell death mechanisms. In addition, GD2 contributes to T-cell dysfunction, and functions as an immune checkpoint. Given the cancer-associated functions, GD2 has been a source of interest for immunotherapy. As a potential biomarker, methods are being developed to quantify GD2 from patients' samples. In addition, various therapeutic strategies are tested. Based on initial success with antibodies, derivates such as bispecific antibodies and immunocytokines have been developed, engaging patient immune system. Cytotoxic effectors or payloads may be redirected based on anti-GD2 antibodies. Finally, vaccines can be used to mount an immune response in patients. We review here the pertinent biological information on GD2 which may be of use for optimizing current immunotherapeutic strategies.

Localization, tissue biology and T cell state - implications for cancer immunotherapy.

Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this has made understanding the factors that dictate T cell function and longevity in tumours challenging. Moreover, T cell differentiation state influences how cues from the microenvironment are interpreted by tissue-infiltrating T cells, highlighting the importance of T cell state in the context of tissue biology. Here, we review the intertwined nature of T cell differentiation state, location, survival and function, and explain how dysfunctional T cell populations can adopt features of tissue-resident memory T cells to persist in tumours. Finally, we discuss how these factors have shaped responses to cancer immunotherapy.

Chronic adrenergic stress and generation of myeloid-derived suppressor cells: Implications for cancer immunotherapy in dogs.

Recent studies have highlighted a key role played by the sympathetic nervous system (SNS) and adrenergic stress in mediating immune suppression associated with chronic inflammation in cancer and other diseases. The connection between chronic SNS activation, adrenergic stress and immune suppression is linked in part to the ability of catecholamines to stimulate the bone marrow release and differentiation of myeloid-derived suppressor cells (MDSC). Rodent model studies have revealed an important role for β-adrenergic receptor signalling in suppression of cancer immunity in mice subjected to chronic stresses, including thermal stress. Importantly, therapeutic blockade of beta-adrenergic responses by drugs such as propranolol can partially reverse the generation and differentiation of MDSC, and partly restore tumour immunity. Clinical trials in both humans and dogs with cancer have demonstrated that propranolol blockade can improve responses to radiation therapy, cancer vaccines and immune checkpoint inhibitors. Thus, the SNS stress response has become an important new target to relieve immune suppression in cancer and other chronic inflammatory conditions.

Synergistic effect of glutathione and IgG4 in immune evasion and the implication for cancer immunotherapy

BackgroundWe recently reported a novel IgG4-centered immune evasion mechanism in cancer, and this was achieved mostly through the Fc-Fc reaction of increased IgG4 to cancer-bound IgG in cancer microenvironment. The mechanism was suggested to be related to cancer hyperprogressive disease (HPD) which is a side-effect often associated to IgG4 subtype PD-1 antibody immunotherapy. HPD was reported to occur in cancers with certain mutated genes including KRAS and such mutations are often associated to glutathione (GSH) synthesis. Therefore, we hypothesize that IgG4 and GSH may play a synergistic role in local immunosuppression of cancer. MethodsQuantitatively analyzed the distribution and abundance of GSH and IgG4 in human cancer samples with ELISA and immunohistochemistry. The interactions between GSH and IgG4 were examined with Electrophoresis and Western Blot. The synergistic effects of the two on classic immune responses were investigated in vitro. The combined effects were also tested in a lung cancer model and a skin graft model in mice. ResultsWe detected significant increases of both GSH and IgG4 in the microenvironment of lung cancer, esophageal cancer, and colon cancer tissues. GSH disrupted the disulfide bond of IgG4 heavy chain and enhanced IgG4’s ability of Fc-Fc reaction to immobilized IgG subtypes. Combined administration of IgG4 and GSH augmented the inhibitory effect of IgG4 on the classic ADCC, ADCP, and CDC reactions. Local administration of IgG4/GSH achieved the most obvious effect of accelerating cancer growth in the mouse lung cancer model. The same combination prolonged the survival of skin grafts between two different strains of mouse. In both models, immune cells and several cytokines were found to shift to the state of immune tolerance. ConclusionCombined application of GSH and IgG4 can promote tumor growth and protect skin graft. The mechanism may be achieved through the effect of the Fc-Fc reaction between IgG4 and other tissue-bound IgG subtypes resulting in local immunosuppression. This reaction was facilitated by increased GSH to dissociate the two heavy chains of IgG4 Fc fragment at its disulfide bonds. Our findings unveiled the interaction between the redox system and the immune systems in cancer microenvironment. It offers a sensible explanation for HPD and provides new possibilities for manipulating this mechanism for cancer immunotherapy.

SETDB1: A perspective into immune cell function and cancer immunotherapy.

Oncogene SET Domain Bifurcated 1 (SETDB1)/ESET, an H3K9 methyltransferase, was originally discovered over two decades ago; however, its function in the immune response was not first reported until 2011. SETDB1 immune functions include B cell maturation, T cell activity regulation, and immune escape in cancer cells. In B lymphocytes, SETDB1 mediates the transition from pro-B to pre-B cells and represses endogenous retroviruses (ERV) to encourage B cell lineage differentiation and maturation. SETDB1 alters T cell function by methylating IL-2 and IL-17 promoters and mediating T cell lineage commitment and development. In addition, SETDB1 plays a critical role in ERV silencing within a variety of immune cells, which can indirectly weaken the immune response. Although SETDB1 is critical for normal immune cell function, overexpression in cancer cells negatively impacts immune cell fights against cancer through decreased tumour immunogenicity. Within cancer cells, SETDB1 overexpression represses production and infiltration of antitumour immune cells, mediates immune escape through TE and ERV silencing, represses the type I interferon pathway, and interferes in immune checkpoint blockade (ICB) outcomes by regulation of PD-L1 expression and IFN signalling. In this review, we further discuss the immunological mechanisms of SETDB1 in normal and cancerous cells and its implications in cancer immunotherapy.

Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy.

Natural killer (NK) cells belong to the early responder group against cancerous cells and viral infection. Emerging evidence reveals that distinct metabolic reprogramming occurs concurrently with activation and memory formation of NK cells. However, metabolism of NK cells is disturbed in the tumor immune microenvironment, which may promote tumor progression while limiting immunotherapy responses. In this review, we highlight how cell metabolism influences NK cell activity, the key molecular regulators of NK cell metabolism, and emerging strategies to alter metabolism to improve cytotoxicity of NK cells to kill tumor cells for cancer patients.

γδ T cells: The potential role in liver disease and implications for cancer immunotherapy.

The γδ T cell subset was discovered over 30 years ago, yet continues to be an exciting and challenging component of the adaptive immune response. While γδ T cells represent a very small fraction of all T cells in humans, γδ T cells have a vital effect on human immunity, serving as a bridge between the innate and adaptive immune systems. The characteristics of γδ T cells include recognition of non-MHC restrictive antigens, as well as the ability to secrete an abundance of cytokines, suggesting that γδ T cells have high antitumor activity. As such, they have gained ample attention with respect to tumor immunotherapy in the last decade. The γδ T cell subset comprises up to ∼15-20% of the T-lymphocyte population in the liver, although the liver is recognized as an immune organ with primary immune functions, the role of γδ T cells in liver disease has not been established. Herein, we present a comprehensive overview of molecular mechanisms underlying immune γδ T cell activity in liver disease, including immune liver injury, viral hepatitis, cirrhosis, and hepatocellular carcinoma, and review γδ T cell-based clinical immunotherapeutic approaches.

New Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy.

Despite rapid advances in the field of immunotherapy, the elimination of established tumors has not been achieved. Many promising new treatments such as adoptive cell therapy (ACT) fall short, primarily due to the loss of T cell effector function or the failure of long-term T cell persistence. With the availability of new tools and advancements in technology, our understanding of metabolic processes has increased enormously in the last decade. Redundancy in metabolic pathways and overlapping targets that could address the plasticity and heterogenous phenotypes of various T cell subsets have illuminated the need for understanding immunometabolism in the context of multiple disease states, including cancer immunology. Herein, we discuss the developing field of T cell immunometabolism and its crucial relevance to improving immunotherapeutic approaches. This in-depth review details the metabolic pathways and preferences of the antitumor immune system and the state of various metabolism-targeting therapeutic approaches.

Differential Macrophage Responses to Gold Nanostars and Their Implication for Cancer Immunotherapy

AbstractGold nanostars (AuNSs) are actively explored for a range of theranostic and nanomedicine applications. While their biological applications are widely demonstrated, the fundamental interactions of these anisotropic nanomaterials with innate immune cells and their implication for cancer immunotherapy are less investigated. Specifically, it remains unclear how AuNSs interact with macrophages of different phenotypes and how these interactions influence the behavior of macrophages, especially their phagocytic and cancer modulating activities. Herein, the interactions between AuNSs of different shapes and macrophages of different phenotypes, including the naïve M0, pro‐inflammatory M1‐like, and anti‐inflammatory M2‐like phenotypes, are systematically interrogated. This study reveals that the morphology of AuNSs significantly impacts their interactions with macrophages. Macrophage viability, oxidative stress response, cytokine release, and phagocytotic ability depend on the macrophage phenotype as well as AuNS shape tip‐to‐core ratio. The selective response of macrophages toward AuNSs, particularly those of M1‐like phenotype, may be potentially leveraged for realizing cancer immunotherapy. Overall, it is anticipated that the findings of this study will further shape the understanding of the interactions between innate immune cells and Au nanomaterials and potentially open new opportunities for cancer therapy.