Comprehensive tumor-immune profiling reveals mediators of paradoxical immune sensitivity in sarcomatoid renal cell carcinoma.

Renal cell carcinoma with sarcomatoid features (sRCC) is a highly aggressive tumor type yet preferentially responds to immune checkpoint blockade (ICB). To better understand microenvironmental mediators of this paradoxical immune sensitivity, we performed single-cell analyses of human sRCC tumors compared against clear cell RCC (ccRCC), with validation spatially and in bulk transcriptomic datasets totaling over 3,000 RCC tumors. We describe a robust immune network in sRCC using these orthogonal approaches: tumor-infiltrating T cells in sRCC are more activated, and subsequently exhausted, while being enriched for CXCL13 expression.

MUC1-C auto-regulatory complex with EBNA1 is responsible for latent Epstein-Barr virus-associated gastric cancer progression.

Latent Epstein-Barr Virus (EBV) infection promotes cancers derived from B-lymphocytes and epithelial cells by mechanisms that largely remain unclear. EBV-encoded nuclear antigen 1 (EBNA1) is uniformly expressed in EBV-associated cancers; however, how EBNA1 contributes to cancer progression is not known. The MUC1 gene evolved in mammals to protect barrier tissues from viral infections.

Targeting FGFR4 abrogates HNF1A-driven metastasis in pancreatic ductal adenocarcinoma.

Background: We previously identified an oncogenic role for the transcription factor HNF1A in pancreatic ductal adenocarcinoma (PDAC). However, the role of HNF1A in the metastatic progression of PDAC remains unknown and targeting modalities for HNF1A-dependent phenotypes have yet to be identified.

Methods: Transwell chambers were used to assess the effects of HNF1A and FGFR4 modulation on the migration and invasion of ATCC and patient-derived PDAC cells in vitro.

MUC1-C dependence in treatment-resistant prostate cancer uncovers a target for antibody-drug conjugate therapy.

Androgen receptor-positive prostate cancer (PC), castration-resistant prostate cancer (CRPC), and neuroendocrine prostate cancer (NEPC) invariably become resistant to treatment with targeted and cytotoxic agents. Multiple pathways have been identified as being responsible for these pleiotropic mechanisms of resistance. The mucin 1 (MUC1) gene is aberrantly expressed in CRPC/NEPC in association with poor clinical outcomes; however, it is not known if the oncogenic MUC1-C/M1C protein drives treatment resistance.

Associations of DNA methylation in breast tumour subtypes with parity and breastfeeding in a cohort of 1459 Black women: implications for public health.

Objective: Having children reduces risk of breast cancer overall, but parity without breastfeeding, more prevalent among black women, increases risk of poor-prognosis oestrogen receptor negative (ER-) breast cancer. We investigated if relationships between parity, breastfeeding and ER subtypes result from epigenetic programming, potentially steering breast progenitor cells to a basal-like phenotype.

Methods And Analysis: The Illumina MethylationEPIC platform was used to assess genome-wide methylation in formalin-fixed, paraffin-embedded tumours from 1459 Black women with breast cancer.

Divergent transcriptional states and kinetics of circulating tumor-infiltrating lymphocyte repertoires with highly homologous T-cell receptor sequences in a patient during immunotherapy.

Evidence has shown that T-cell receptors (TCRs) that recognize the same epitopes may not be the exact TCR clonotypes but have slightly different TCR sequences. However, the changes in the genomic and transcriptomic signatures of these highly homologous T cells during immunotherapy remain unknown. Here, we examined the evolutionary features in circulating TCR clonotypes observed in tumors (tumor-infiltrating lymphocyte (TIL)-TCRs) by combining single-cell RNA/TCR sequencing of longitudinal blood samples and TCR sequencing of tumor tissue from a patient treated with anti-cytotoxic T-lymphocyte-associated protein 4/programmed cell death protein-1 therapy.

Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer.

Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers.

NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.

Cytotoxic CD8+ T lymphocyte (CTL) recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells and also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes and long-term survival of patients with melanoma. Using MART1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs.

A Senescence-Mimicking (Senomimetic) VEGFR TKI Side Effect Primes Tumor Immune Responses via IFN/STING Signaling.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) not only disrupt tumor angiogenesis but also have many unexpected side effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance.

Generation, Transcriptomic States, and Clinical Relevance of CX3CR1+ CD8 T Cells in Melanoma.

Unlabelled: Recent progress in single-cell profiling technologies has revealed significant phenotypic and transcriptional heterogeneity in tumor-infiltrating CD8+ T cells. However, the transition between the different states of intratumoral antigen-specific CD8+ T cells remains elusive. Here, we sought to examine the generation, transcriptomic states, and the clinical relevance of melanoma-infiltrating CD8+ T cells expressing a chemokine receptor and T-cell differentiation marker, CX3C chemokine receptor 1 (CX3CR1).

A senescence-mimicking (senomimetic) VEGFR TKI side-effect primes tumor immune responses via IFN/STING signaling.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) disrupt tumor angiogenesis but also have many unexpected side-effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence-markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance.

Identification of MUC1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas.

Unlabelled: The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCC). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCC).

The predominant Quillaja Saponaria fraction, QS-18, is safe and effective when formulated in a liposomal murine cancer peptide vaccine.

Extracts of the Chilean soapbark tree, Quillaja Saponaria (QS) are the source of potent immune-stimulatory saponin compounds. This study compared the adjuvanticity and toxicity of QS-18 and QS-21, assessing the potential to substitute QS-18 in place of QS-21 for vaccine development. QS-18, the most abundant QS saponin fraction, has been largely overlooked due to safety concerns.

Identification of Enhanced Vaccine Mimotopes for the p15E Murine Cancer Antigen.

Unlabelled: Mimotopes of short CD8+ T-cell epitopes generally comprise one or more mutated residues, and can increase the immunogenicity and function of peptide cancer vaccines. We recently developed a two-step approach to generate enhanced mimotopes using positional peptide microlibraries and herein applied this strategy to the broadly used H-2Kb-restricted murine leukemia p15E tumor rejection epitope. The wild-type p15E epitope (sequence: KSPWFTTL) was poorly immunogenic in mice, even when combined with a potent peptide nanoparticle vaccine system and did not delay p15E-expressing MC38 tumor growth.

Leukemic mutation FLT3-ITD is retained in dendritic cells and disrupts their homeostasis leading to expanded Th17 frequency.

Dendritic cells (DC) are mediators between innate and adaptive immune responses to pathogens and tumors. DC development is determined by signaling through the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3) in bone marrow myeloid progenitors. Recently the naming conventions for DC phenotypes have been updated to distinguish between "Conventional" DCs (cDCs) and plasmacytoid DCs (pDCs).

Stratification of Patients with Renal Cell Carcinoma by the Abundance of Sarcomatoid Features Reveals Differences in Survival and the Underlying Pathobiology.

Sarcomatoid renal cell carcinoma (sRCC) is histologically heterogeneous, with variable sarcomatoid amounts intermixed within epithelial carcinoma. However, the current classification for this aggressive disease is homogeneous and agnostic to the sarcomatoid proportion. We investigated whether sRCC subclassification has prognostic value and can reveal the biology underlying dedifferentiation and its clinical aggressiveness.

Clinical and immunological relevance of SLAMF6 expression in the tumor microenvironment of breast cancer and melanoma.

Compelling evidence shows that the frequency of T cells in the tumor microenvironment correlates with prognosis as well as response to immunotherapy. However, considerable heterogeneity exists within tumor-infiltrating T cells, and significance of their genomic and transcriptomic landscape on clinical outcomes remains to be elucidated. Signaling lymphocyte activation molecule 6 (SLAMF6) is expressed on intra-tumoral progenitor-exhausted T cells, which exhibit the capacity to proliferate, self-renew and produce terminally-exhausted T cells in pre-clinical models and patients.

Epigenetic disruption of the RARγ complex impairs its function to bookmark AR enhancer interactions required for enzalutamide sensitivity in prostate cancer.

The current study in prostate cancer (PCa) focused on the genomic mechanisms at the cross-roads of pro-differentiation signals and the emergence of lineage plasticity. We explored an understudied cistromic mechanism involving RARγ's ability to govern AR cistrome-transcriptome relationships, including those associated with more aggressive PCa features. The RARγ complex in PCa cell models was enriched for canonical cofactors, as well as proteins involved in RNA processing and bookmarking.

Aryl hydrocarbon receptor is a tumor promoter in -amplified neuroblastoma cells through suppression of differentiation.

Neuroblastoma is the most common extracranial solid tumor in children. amplification is detected in almost half of high-risk cases and is associated with poorly differentiated tumors, poor patient prognosis and poor response to therapy, including retinoids. We identify the aryl hydrocarbon receptor (AhR) as a transcription factor promoting the growth and suppressing the differentiation of -amplified neuroblastoma.

The MYC axis in advanced prostate cancer is impacted through concurrent targeting of ERβ and AR using a novel ERβ-selective ligand alongside Enzalutamide.

We have dissected the role of Estrogen receptor beta (ERβ) in prostate cancer (PCa) with a novel ERβ ligand, OSU-ERb-12. Drug screens revealed additive interactions between OSU-ERB-12 and either epigenetic inhibitors or the androgen receptor antagonist, Enzalutamide (Enza). Clonogenic and cell biolody studies supported the potent additive effects of OSU-ERB-12 (100nM) and Enza (1μM).

MUC1-C integrates aerobic glycolysis with suppression of oxidative phosphorylation in triple-negative breast cancer stem cells.

Activation of the MUC1-C protein promotes lineage plasticity, epigenetic reprogramming, and the cancer stem cell (CSC) state. The present studies performed on enriched populations of triple-negative breast cancer (TNBC) CSCs demonstrate that MUC1-C is essential for integrating activation of glycolytic pathway genes with self-renewal and tumorigenicity. MUC1-C further integrates the glycolytic pathway with suppression of mitochondrial DNA (mtDNA) genes encoding components of mitochondrial Complexes I-V.

MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression.

Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated by the inflammatory NF-κB pathway in cancer cells. There is no known involvement of MUC1-C in regulation of the COMPASS family of H3K4 methyltransferases.

Leukemic mutation FLT3-ITD is retained in dendritic cells and disrupts their homeostasis leading to expanded Th17 frequency.

Dendritic cells (DC) are mediators of adaptive immune responses to pathogens and tumors. DC development is determined by signaling through the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3) in bone marrow myeloid progenitors. Recently the naming conventions for DC phenotypes have been updated to distinguish between "Conventional" DCs (cDCs) and plasmacytoid DCs (pDCs).

Mass Cytometry reveals unique phenotypic patterns associated with subclonal diversity and outcomes in multiple myeloma.

Multiple myeloma (MM) remains an incurable plasma cell (PC) malignancy. Although it is known that MM tumor cells display extensive intratumoral genetic heterogeneity, an integrated map of the tumor proteomic landscape has not been comprehensively evaluated. We evaluated 49 primary tumor samples from newly diagnosed or relapsed/refractory MM patients by mass cytometry (CyTOF) using 34 antibody targets to characterize the integrated landscape of single-cell cell surface and intracellular signaling proteins.