Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

The crosstalking immune cells network creates a collective function beyond the function of each cellular constituent during the progression of hepatocellular carcinoma.

Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of focusing on detailed specific cell types and missing the collective function of the hepatic immune system. To discover the collective immune function, we take systems immunology approach by performing high-throughput analysis of snRNAseq data collected from the liver of DIAMOND mice during the progression of nonalcoholic fatty liver disease (NAFLD) to HCC. We report that mutual signaling interactions of the hepatic immune cells in a dominant-subdominant manner, as well as their interaction with structural cells shape the immunological pattern manifesting a collective function beyond the function of the cellular constituents. Such pattern discovery approach recognized direct role of the innate immune cells in the progression of NASH and HCC. These data suggest that discovery of the immune pattern not only detects the immunological mechanism of HCC in spite of dynamic changes in immune cells during the course of disease but also offers immune modulatory interventions for the treatment of NAFLD and HCC.

From Reductionistic Approach to Systems Immunology Approach for the Understanding of Tumor Microenvironment.

The tumor microenvironment (TME) is a complex and dynamic ecosystem that includes a variety of immune cells mutually interacting with tumor cells, structural/stromal cells, and each other. The immune cells in the TME can have dual functions as pro-tumorigenic and anti-tumorigenic. To understand such paradoxical functions, the reductionistic approach classifies the immune cells into pro- and anti-tumor cells and suggests the therapeutic blockade of the pro-tumor and induction of the anti-tumor immune cells. This strategy has proven to be partially effective in prolonging patients' survival only in a fraction of patients without offering a cancer cure. Recent advances in multi-omics allow taking systems immunology approach. This essay discusses how a systems immunology approach could revolutionize our understanding of the TME by suggesting that internetwork interactions of the immune cell types create distinct collective functions independent of the function of each cellular constituent. Such collective function can be understood by the discovery of the immunological patterns in the TME and may be modulated as a therapeutic means for immunotherapy of cancer.

The Adaptation Model of Immunity: Signal IV Matters Most in Determining the Functional Outcomes of Immune Responses.

Current research in immunology and immunotherapy is fully influenced by the self-nonself model of immunity. This theoretical model suggests that alloreactivity results in graft rejection, whereas tolerance toward self-antigens expressed by malignant cells facilitates cancer development. Similarly, breakage of immunological tolerance toward self-antigens results in autoimmune diseases. Accordingly, immune suppression is recommended for the management of autoimmune diseases, allergy, and organ transplantation, whereas immune inducers are used for the treatment of cancers. Although the danger model, the discontinuity model, and the adaptation model are proposed for a better understanding of the immune system, the self-nonself model continues to dominate the field. Nevertheless, a cure for these human diseases remains elusive. This essay discusses current theoretical models of immunity, as well as their impacts and limitations, and expands on the adaptation model of immunity to galvanize a new direction for the treatment of autoimmune diseases, organ transplantation, and cancer.

SRA inhibition improves antitumor potency of antigen-targeted chaperone vaccine.

We have previously demonstrated that scavenger receptor A (SRA) acts as an immunosuppressive regulator of dendritic cell (DC) function in activating antitumor T cells. Here we investigate the potential of inhibiting SRA activity to enhance DC-targeted chaperone vaccines including one that was recently evaluated in melanoma patients. We show that short hairpin RNA-mediated SRA silencing significantly enhances the immunogenicity of DCs that have captured chaperone vaccines designed to target melanoma (i.e., hsp110-gp100) and breast cancer (i.e., hsp110-HER/Neu-ICD). SRA downregulation results in heightened activation of antigen-specific T cells and increased CD8+ T cell-dependent tumor inhibition. Additionally, small interfering RNA (siRNA) complexed with the biodegradable, biocompatible chitosan as a carrier can efficiently reduce SRA expression on CD11c+ DCs in vitro and in vivo. Our proof-of-concept study shows that direct administration of the chitosan-siRNA complex to mice promotes chaperone vaccine-elicited cytotoxic T lymphocyte (CTL) response, culminating in improved eradication of experimental melanoma metastases. Targeting SRA with this chitosan-siRNA regimen combined with the chaperone vaccine also leads to reprogramming of the tumor environment, indicated by elevation of the cytokine genes (i.e., ifng, il12) known to skew Th1-like cellular immunity and increased tumor infiltration by IFN-γ+CD8+ CTLs as well as IL-12+CD11c+ DCs. Given the promising antitumor activity and safety profile of chaperone vaccine in cancer patients, further optimization of the chitosan-siRNA formulation to potentially broaden the immunotherapeutic benefits of chaperone vaccine is warranted.

The adaptation model of immunity: A new insight into aetiology and treatment of multiple sclerosis.

Current research and drug development for multiple sclerosis (MS) is fully influenced by the self-nonself (SNS) model of immunity, suggesting that breakage of immunological tolerance towards self-antigens expressed in the central nervous system (CNS) is responsible for pathogenesis of MS; thus, immune suppressive drugs are recommended for the management of the disease. However, this model provides incomplete understanding of the causes and pathways involved in the onset and progression of MS and limits our ability to effectively treat this neurological disease. Some pre-clinical and clinical reports have been misunderstood; some others have been underappreciated because of the lack of a theoretical model that can explain them. Also, current immunotherapies are guided according to the models that are not designed to explain the functional outcomes of an immune response. The adaptation model of immunity is proposed to offer a new understanding of the existing data and galvanize a new direction for the treatment of MS. According to this model, the immune system continuously communicates with the CNS through the adaptation receptors (AdRs) and adaptation ligands (AdLs) or co-receptors, signal IV, to support cell growth and neuroplasticity. Alterations in the expression of the neuronal AdRs results in MS by shifting the cerebral inflammatory immune responses from remyelination to demyelination. Therefore, novel therapeutics for MS should be focused on the discovery and targeting of the AdR/AdL axis in the CNS rather than carrying on with immune suppressive interventions.

Restoration of CD4+ T Cells during NAFLD without Modulation of the Hepatic Immunological Pattern Is Not Sufficient to Prevent HCC.

Predominant inflammatory immunological patterns as well as the depletion of CD4+ T cells during nonalcoholic fatty liver disease (NAFLD) are reported to be associated with the progression of hepatocellular carcinoma (HCC). Here, we report that an LRP-1 agonistic peptide, SP16, when administered during advanced NAFLD progression, restored the depleted CD4+ T cell population but did not significantly affect the inflammatory immunological pattern. This data suggests that restoration of CD4+ T cells without modulation of the hepatic immunological pattern is not sufficient to prevent HCC. However, SP16 administered early during NAFLD progression modulated the inflammatory profile. Future studies will determine if regulation of the inflammatory immune response by SP16 early in NAFLD progression will prevent HCC.

The adaptation model of immunity: Is the goal of central tolerance to eliminate defective T cells or self-reactive T cells?

The self-non-self model and the danger model are designed to understand how an immune response is induced. These models are not meant to predict if an immune response may succeed or fail in destroying/controlling its target. However, these immunological models rely on either self-antigens or self-dendritic cells for understanding of central tolerance, which have been discussed by Fuchs and Matzinger in response to Al-Yassin. In an attempt to address some questions that these models are facing when it comes to understanding central tolerance, I propose that the goal of negative selection in the thymus is to eliminate defective T cells but not self-reactive T cells. Therefore, any escape from negative selection could increase lymphopenia because of the depletion of defective naïve T cells outside the thymus, as seen in the elderly.

Distinct hepatic immunological patterns are associated with the progression or inhibition of hepatocellular carcinoma.

To discover distinct immune responses promoting or inhibiting hepatocellular carcinoma (HCC), we perform a three-dimensional analysis of the immune cells, correlating immune cell types, interactions, and changes over time in an animal model displaying gender disparity in nonalcoholic fatty liver disease (NAFLD)-associated HCC. In response to a Western diet (WD), animals mount acute and chronic patterns of inflammatory cytokines, respectively. Tumor progression in males and females is associated with a predominant CD8+ > CD4+, Th1 > Th17 > Th2, NKT > NK, M1 > M2 pattern in the liver. A complete rescue of females from HCC is associated with an equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern, while a partial rescue of males from HCC is associated with an equilibrium CD8+ = CD4+, NKT = NK and a semi-equilibrium Th1 = Th17 > Th2 but a sustained M1 > M2 pattern in the liver. Our data suggest that immunological pattern-recognition can explain immunobiology of HCC and guide immune modulatory interventions for the treatment of HCC in a gender-specific manner.

Pattern recognition of tumor dormancy and relapse beyond cell-intrinsic and cell-extrinsic pathways.

In this thematic issue, several mechanisms of tumor dormancy and relapse are discussed. The reviews suggest mutual interactions and communications between malignant cells and other cells in their niche during tumor dormancy. Nevertheless, a complete understanding of tumor dormancy remains elusive. This is because we are getting lost in details of cell-intrinsic and cell-extrinsic molecular pathways without being able to discover the pattern of tumor dormancy. Here, we discuss some conceptual frameworks and methodological approaches that facilitate pattern recognition of tumor dormancy, and propose that settling on certain biological scale such as mitochondria would be the key to discover the pattern of tumor dormancy and relapse.

Multifaceted functions of chronic inflammation in regulating tumor dormancy and relapse.

Inflammation is a double-edged sword exhibiting multifaceted functions. On one hand, it either induces tumor cell apoptosis, or establishes tumor dormancy by inhibiting tumor cell proliferation; on the other hand, it either facilitates the tumorigenesis process or reawakens dormant tumor cells, resulting in disease recurrences. Each outcome would depend on the balance between type I and type II inflammation as well as the duration of inflammation being acute or chronic. In this essay, we provide a critical review of the empirical evidence suggesting that chronic inflammation, dominated by type I inflammatory cells and cytokines as a result of trauma and microbiome dysbiosis, could facilitate the carcinogenesis process in normal cells and retain nascent transformed cells in a dormant state. On the other hand, an elevated type II inflammation along with inefficient resolution of type I inflammation following trauma or major surgeries could delay the wound healing process and promote the growth and reawakening of dormant tumor cells, resulting in disease recurrences. Finally, cytokines exhibiting type I and II inflammatory functions, simultaneously, tend to promote tumor recurrence when become chronic. Therefore, the risk of reawakening dormant tumor cells should be considered in cancer survivors who experience major surgeries and trauma, or suffer from chronic inflammatory diseases.

Engineering T Cells to Express Tumoricidal MDA-7/IL24 Enhances Cancer Immunotherapy.

Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation-associated gene-7/IL24 (MDA-7/IL24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL24-potentiated T-cell expansion was dependent on T-cell-intrinsic STAT3 signaling. Finally, MDA-7/IL24-modified T-cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T-cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape. SIGNIFICANCE: This research describes a novel strategy to overcome the antigenic heterogeneity of solid cancers and prevent tumor escape by engineering T lymphocytes to produce a broad-spectrum tumoricidal agent.

Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets.

BACKGROUND: Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy. METHODS: We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells. RESULTS: We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67- and Ki67low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs. CONCLUSION: Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation.

Radiation is a critical pillar in cancer therapeutics, exerting its anti-tumor DNA-damaging effects through various direct and indirect mechanisms. Radiation has served as an effective mode of treatment for a number of cancer types, providing both curative and palliative treatment; however, resistance to therapy persists as a fundamental limitation. While cancer cell death is the ideal outcome of any anti-tumor treatment, radiation induces several responses, including apoptotic cell death, mitotic catastrophe, autophagy and senescence, where autophagy and senescence may promote cell survival. In most cases, autophagy, a conventionally cytoprotective mechanism, is a "first" responder to damage incurred from chemotherapy and radiation treatment. The paradigm developed on the premise that autophagy is cytoprotective in nature has provided the rationale for current clinical trials designed with the goal of radiosensitizing cancer cells through the use of autophagy inhibitors; however, these have failed to produce consistent results. Delving further into pre-clinical studies, autophagy has actually been shown to take diverse, sometimes opposing, forms, such as acting in a cytotoxic or nonprotective fashion, which may be partially responsible for the inconsistency of clinical outcomes. Furthermore, autophagy can have both pro- and anti-tumorigenic effects, while also having an important immune modulatory function. Senescence often occurs in tandem with autophagy, which is also the case with radiation. Radiation-induced senescence is frequently followed by a phase of proliferative recovery in a subset of cells and has been proposed as a tumor dormancy model, which can contribute to resistance to therapy and possibly also disease recurrence. Senescence induction is often accompanied by a unique secretory phenotype that can either promote or suppress immune functions, depending on the expression profile of cytokines and chemokines. Novel therapeutics selectively cytotoxic to senescent cells (senolytics) may prove to prolong remission by delaying disease recurrence in patients. Accurate assessment of primary responses to radiation may provide potential targets that can be manipulated for therapeutic benefit to sensitize cancer cells to radiotherapy, while sparing normal tissue.

COVID-19 as an Acute Inflammatory Disease.

The 2019 coronavirus disease (COVID-19) pandemic caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created an unprecedented global crisis for the infrastructure sectors, including economic, political, healthcare, education, and research systems. Although over 90% of infected individuals are asymptomatic or manifest noncritical symptoms and will recover from the infection, those individuals presenting with critical symptoms are in urgent need of effective treatment options. Emerging data related to mechanism of severity and potential therapies for patients presenting with severe symptoms are scattered and therefore require a comprehensive analysis to focus research on developing effective therapeutics. A critical literature review suggests that the severity of SARS-CoV-2 infection is associated with dysregulation of inflammatory immune responses, which in turn inhibits the development of protective immunity to the infection. Therefore, the use of therapeutics that modulate inflammation without compromising the adaptive immune response could be the most effective therapeutic strategy.

The premise of personalized immunotherapy for cancer dormancy.

Progress in cancer therapies has resulted in improved survival of patients with early stage breast cancer. However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment of early stage breast cancer. To this end, tumor recurrences have been attributed to the presence of dormant tumor cells in breast cancer patients and cancer survivors. Current clinical practice guidelines recommend a "wait-and-watch" approach for tumor recurrence. This is because of our limited understanding of tumor dormancy. Dormant tumor cells are quiescent, and thus, do not respond to chemotherapies or radiation therapies, and they are not operable. Therefore, immunotherapy is the only option for the treatment of tumor dormancy. However, gaps in our knowledge as to dormancy-specific antigens prevent a relapse preventing vaccine design. Here, I provide a critical review of cancer immunotherapy, and discuss empirical evidence related to naturally occurring tumor dormancy and treatment-induced tumor dormancy at the site of primary tumor and in distant organs before and after cancer therapies. Finally, I suggest that personalized vaccines targeting dormancy-associated neoantigens, which can be given to patients with early stage disease after the completion of neoadjuvant therapies and tumor resection as well as to cancer survivors could eliminate relapse causing dormant cells and offer a cure for cancer.

Longitudinal studies can identify distinct inflammatory cytokines associated with the inhibition or progression of liver cancer.

BACKGROUND AND AIMS: Chronic diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are associated with chronic inflammation. However, controversial reports as to the key cytokines involved in the process of chronic inflammation hinder development of targeted therapies for patients. This is because, chronic inflammatory process cannot be fully understood by studying the mechanisms of the disease in a short-term or isolated fashion. Understanding of the trend of inflammatory cytokines through longitudinal studies could provide a profound insight into the process of disease progression. METHODS: We performed a longitudinal analysis of inflammatory cytokines/chemokines and faecal microbiome dysbiosis associated with the diet-induced progression of NAFLD to HCC in diet-induced animal model of NAFLD comparing males and females, since males show a higher incidence of these diseases than females do. RESULTS: Longitudinal analyses revealed that a transient and timely increase in LIF and TMIP1 was associated with the inhibition of the progression of NAFLD to HCC in females. On the other hand, chronically increasing trends in CCL12, CCL17, CXCL9 and LIX/CXCL5 were associated with the promotion of the progression of NAFLD to HCC in males. CONCLUSIONS: We provided empirical evidence that a methodological shift from snapshot observations to longitudinal data collection and analysis can provide a better understanding of chronic liver diseases.

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including angiogenic switch, immune escape, cancer stem cells, extracellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer and discuss the implications of such approaches in cancer treatment.

The microbiome and breast cancer: a review.

The human microbiome plays an integral role in physiology, with most microbes considered benign or beneficial. However, some microbes are known to be detrimental to human health, including organisms linked to cancers and other diseases characterized by aberrant inflammation. Dysbiosis, a state of microbial imbalance with harmful bacteria species outcompeting benign bacteria, can lead to maladies including cancer. The microbial composition varies across body sites, with the gut, urogenital, and skin microbiomes particularly well characterized. However, the microbiome associated with normal breast tissue and breast diseases is poorly understood. Collectively, studies have shown that breast tissue has a distinct microbiome with particular species enriched in the breast tissue itself, as well as the nipple aspirate and gut bacteria of women with breast cancer. More importantly, the breast and associated microbiomes may modulate therapeutic response and serve as potential biomarkers for diagnosing and staging breast cancer.

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation.

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation.