Cancer Surveillance Research Articles

Mitochondrial regulation in the tumor microenvironment: targeting mitochondria for immunotherapy

Mitochondrial regulation plays a crucial role in cancer immunity in the tumor microenvironment (TME). Infiltrating immune cells, including T cells, natural killer (NK) cells, and macrophages, undergo mitochondrial metabolic reprogramming to survive the harsh conditions of the TME and enhance their antitumor activity. On the other hand, immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), mast cells, and tumor-associated macrophages (TAMs) rely on mitochondrial regulation to maintain their function as well. Additionally, mitochondrial regulation of cancer cells facilitates immune evasion and even hijacks mitochondria from immune cells to enhance their function. Recent studies suggest that targeting mitochondria can synergistically reduce cancer progression, especially when combined with traditional cancer therapies and immune checkpoint inhibitors. Many mitochondrial-targeting drugs are currently in clinical trials and have the potential to enhance the efficacy of immunotherapy. This mini review highlights the critical role of mitochondrial regulation in cancer immunity and provides lists of mitochondrial targeting drugs that have potential to enhance the efficacy of cancer immunotherapy.

Cancer in multi-lineage mosaic RASopathies due to pathogenic variants in HRAS or KRAS: a systematic review and meta-analysis.

To determine the cancer risk and spectrum in patients with multi-lineage mosaic RASopathies with pathogenic variants (PV) in HRAS or KRAS. We conducted a systematic literature review to identify multi-lineage mosaic RASopathy cases with a PV in HRAS or KRAS to create a retrospective cohort. We calculated cumulative incidence, cancer-free survival and hazard rates (HR) for cancer and standardized incidence rates (SIR). This study identified 69 patients. Seventeen percent had cancer, including rhabdomyosarcoma located in the urogenital region (n=7), skin cancer (n=3), Wilms tumor (n=1), and bladder cancer (n=1). Cumulative cancer incidence by age 20 was 20% (95% CI, 4 to 37%). The annual cancer HR peaked at 14% within the first two years of life. The highest SIR was found for rhabdomyosarcoma (SIR = 800, 95% CI, 300 to 1648). This is the first investigation of cancer risk in KRAS or HRAS PV-positive mosaic RASopathies to date. The high incidence and SIR values found highlight the need for rigorous rhabdomyosarcoma surveillance in young children and skin cancer surveillance in adults with this high-risk condition.

Targeted Biopsy Is Sufficient for Men on Active Surveillance for Early-Stage Prostate Cancer.

Serial biopsy is a mainstay for patients on active surveillance (AS) for prostate cancer. mpMRI targeting has become a standard. It is unclear whether targeted biopsy alone reliably identifies the dominant lesion, thereby obviating the need for systematic sampling. Participants enrolled in AS with early-stage prostate cancer (PSA < 20, cT1-2, GG1-2) and underwent 2+ systematic biopsy sessions with or without MR-targeted sampling. The findings for dominant Gleason Grade (GG) and tumor localization were assessed. Among 821 men who underwent MR fusion biopsies, 82% were diagnosed with GG1 and 18% with GG2. Sixty-two percent had their first MR fusion biopsy as diagnostic or confirmatory. Across all fusion biopsies, MRI-targeted detection of GG and/or tumor location overlapped with systematic sampling for 95% of cases. For 5% of cases, systematic biopsy was unique in detecting GG and location outside the target. Most unique lesions detected outside the target had marginally aggressive features: 73% GG2 of low-volume and favorable histologic subtypes. In men with MR fusion biopsies, targeting alone identified the dominant GG and location most of the time (95%); 25% of dominant lesions were contiguous to the target, suggesting that better sampling of the target improves detection. The remaining 5% of men had higher-grade, low-volume disease outside the targeted lesion of which only 2% had aggressive risk features. MR fusion targeting, without systematic sampling, may be sufficient to monitor men on AS. Few high-risk cancers are missed, all of limited volume and favorable histology.

MicroEpitope: an atlas of immune epitopes derived from cancer microbiomes.

The majority of human cancers harbor molecular evidence of intratumoral microbiota. Microbiota-derived epitopes as molecular mimics of tumor antigens can bind human leukocyte antigen (HLA), thereby modulating host immunity. However, many questions remain regarding the mechanisms underlying the interactions between microbiota and the host's immune system in cancer. Here, MicroEpitope (http://bio-bigdata.hrbmu.edu.cn/MicroEpitope) was developed to provide and analyze the atlas of microbiota-derived epitopes in cancer. We manually collected available mass spectrometry (MS)-based HLA immunopeptidomes of 1190 samples across 24 cancer types. Alignment was performed against an in-house constructed theoretical library of human and intratumor microbiome encoded proteins, including 1298 bacterial and 124 viral species. Currently, MicroEpitope contains 51497 bacteria and 767 virus-derived epitopes, mainly originating from Bacillus subtilis, Buchnera aphidicolaand human cytomegalovirus. The common immunogenic features of epitopes were calculated, as well as their biochemical properties and the clinical relevance of corresponding bacteria and viruses across cancers. MicroEpitope also provides five analytical tools, and multiple visualization methods to facilitate understanding of the roles of microbiota-derived epitopes in cancer immunity. In summary, MicroEpitope represents a vital resource for investigating HLA-presented immunopeptidomes derived from cancer microbiomes, and could further enable rich insight in tumor antigen prioritization strategies.

Immune-reactive tumor organoids system to determine the effects of microbial metabolites on cancer immunity and immunotherapies

Immunotherapies are a revolutionary approach to treating cancer by utilizing the body’s immune system to target and combat cancer cells. This approach offers promising alternatives to traditional chemotherapies. Its potential to induce long-lasting remissions and specificity for cancer cells, which minimizes side effects, makes it a cutting-edge treatment with tremendous potential. With the increase of the clinical usage of immunotherapy, evidence emerges of the microbiome’s impact on both tumor growth and response to immunotherapy. The proposed involvement of the microbiome can change treatment efficacy by altering drug metabolism and reshaping the immune system response. Understanding the specific interactions between tumor cells, immune cells, and the microbiome is a critical step in the advancement of immunotherapy. To study the complex interaction between cancer immunity and the microbiome, various preclinical in vivo and in vitro models have been developed. We have recently described the use of an ex vivo preclinical model for anti-cancer treatment outcome prediction –tumor tissue equivalents (organoids). Specifically, immune-reactive tumor organoids are proposed as a novel tool for understanding how the microbiome influences cancer immunity and immunotherapy. More importantly, this platform can utilize patient samples to dissect patient-specific elements regulating cancer immune response and microbiome influence. This review presents the rationale for using the immune-reactive tumor organoids model to study the interactions between the microbiome and cancer immunotherapy. It will discuss available components of the model and analyze their interplay, summarize relevant experimental data, and assess their validity. Additionally, it explores the potential of immune-reactive organoids for personalized treatment approaches. Understanding the microbiome’s role in immunotherapy outcomes will lead to transformative cancer treatment via a simple change of diet or other microbiome manipulations. Ongoing research on microbiome-cancer interactions utilizing the described model systems will lead to innovative treatment strategies and improved patient outcomes.

Induced Necroptosis and Its Role in Cancer Immunotherapy

Necroptosis is a type of regulated cell death (RCD) that is triggered by changes in the extracellular or intracellular milieu that are picked up by certain death receptors. Thanks to its potent capacity to induce immunological responses and overcome apoptotic resistance, it has garnered significant attention as a potential cancer treatment. Basic information for the creation of nano-biomedical treatments is provided by studies on the mechanisms underlying tumor necroptosis. Receptor-interacting protein kinase 1 (RIPK1)–RIPK3-mediated necroptosis, Toll-like receptor domain-containing adapter-inducing interferon (IFN)-β (TRIF)–RIPK3-mediated necroptosis, Z-DNA-binding protein 1 (ZBP1)–RIPK3-mediated necroptosis, and IFNR-mediated necroptosis are the four signaling pathways that collectively account for triggered necroptosis in this review. Necroptosis has garnered significant interest as a possible cancer treatment strategy because, in contrast to apoptosis, it elicits immunological responses that are relevant to therapy. Thus, a thorough discussion is held on the connections between tumor cell necroptosis and the immune environment, cancer immunosurveillance, and cells such as dendritic cells (DCs), cytotoxic T cells, natural killer (NK) cells, natural killer T (NKT) cells, and their respective cytokines. Lastly, a summary of the most recent nanomedicines that cause necroptosis in order to cause immunogenic cell death is provided in order to emphasize their promise for cancer immunotherapy.

The Relationship Between Anti-Cell Division Cycle and Apoptosis Regulator 1 Autoantibodies, Anti-Sp4 Autoantibodies, and Cancer in Anti-Transcription Intermediary Factor 1γ-Positive Dermatomyositis.

The objective of this study was to describe the frequency, co-occurrence, and cancer association of anti-cell division cycle and apoptosis regulator 1 (anti-CCAR1) and anti-Sp4 in two large independent adult dermatomyositis (DM) cohorts. Anti-transcription intermediary factor 1γ (anti-TIF1γ)-positive patients with DM from two independent cohorts were studied to determine the serologic overlap of anti-CCAR1 and anti-Sp4 autoantibodies measured by enzyme-linked immunosorbent assay. Associations between cancer-associated myositis (CAM) and antibody-defined subgroups within anti-TIF1γ-positive patients with DM were determined. A total of 305 anti-TIF1γ-positive patients with DM were studied: 169 patients from Johns Hopkins and 136 patients from Stanford. In each cohort, approximately one-third of anti-TIF1γ-positive patients with DM were anti-Sp4 positive, one-third were anti-CCAR1 positive, 20% were positive for both, and half of patients were negative for both. There was a strong association with CAM in patients lacking both these antibodies (Johns Hopkins, odds ratio [OR] 12.9 [95% confidence interval (CI) 3.6-89.5]; Stanford, OR 4.5 [95% CI 1.8-13.2]). The strongest negative association with CAM was found in patients with anti-Sp4 or anti-CCAR1 (Johns Hopkins, OR 0.07 [95% CI 0.01-0.27]; Stanford, OR 0.22 [95% CI 0.07-0.55]). Both anti-Sp4 and anti-CCAR1 autoantibody subgroups are negatively associated with CAM. Although the magnitude of this association is substantial, cancer occasionally occurs in patients positive for either specificity. Conversely, approximately half of anti-TIF1γ-positive patients with DM are negative for both antibodies (anti-Sp4/anti-CCAR1 negative), and thus this subgroup may warrant more intensive cancer surveillance.

Neudesin regulates dendritic cell function and antitumor CD8+ T cell immunity

Dendritic cells (DCs) are essential for antitumor T-cell responses to immune checkpoint inhibitor therapies. We have previously reported that the secreted protein neudesin suppresses DC function. In contrast, neudesin has been found to be abundantly expressed in human cancers. In this study, we evaluated the role of neudesin in cancer immunity. Cancer-related database analysis revealed that patients with melanoma with low neudesin expression exhibited increased infiltration of DCs and CD8+ T cells and improved outcomes of checkpoint inhibitor therapy. In mouse tumor models, neudesin deficiency delayed tumor growth and increased the proportions of Type 1 conventional DCs (cDC1s) and tumor antigen-specific CD8+ T cells in tumors and tumor-infiltrating lymph nodes. Neudesin-deficient antitumor cDC1 vaccine enhanced the systemic immunity more effectively than the wild-type cDC1 vaccine. Overall, our findings highlight the importance of neudesin in cancer immunity, providing a novel target for immunotherapy.

Immune-related glycosylation genes based classification predicts prognosis and therapy options of osteosarcoma

Osteosarcoma is the most common primary bone malignancy, with a very poor prognosis. Aberrant glycosylation is close involvement in osteosarcoma. Accordingly, this study aimed at investigating the role of glycosylation genes in the prognosis and therapy options of osteosarcoma. The microenvironment of osteosarcoma was assessed using estimate algorithm. A total of 20 immune-related glycosylation genes (IRGGs) was identified using Pearson correlation analysis. Accordingly, osteosarcoma patients were divided into C1 and C2 type using consensus clustering. Multiple algorithms (Xcell, MCP-counter, ssGSEA, epic, quantiseq), cancer immune cycle analysis, and GSVA were applied to estimate the immune, molecule and metabolism characteristics of osteosarcoma, indicating that C1 type was featured with high immune infiltration, high glycosylation, enriched MEK signaling, and good prognosis, while C2 type was characterized by more metastasis, enriched immunotherapy-positive gene signatures, high tumor mutation burden, and poor prognosis. Results from TIDE algorithm and immunotherapy datasets suggested the C2 type’s preference of immune checkpoint inhibitors (ICIs), while data of GDSC, CMap analysis and cell experiments indicated that C1 type was sensitivity to MEK inhibitor PD0325901. In addition, univariate Cox and Lasso analysis was combined to establish an IRGGs’ risk score containing 6 genes (B3GNT8, FUT7, GAL3ST4, GALNT14, HS3ST2, and MFNG). The data of DCA and ROC indicated its well prediction of prognosis in osteosarcoma. Finally, cellular location analysis showed that the 6 genes not only distributed in tumor cells but also in immune cells. In summary, the classification and risk score based on IRGGs effectively predicted the prognosis and therapy options of osteosarcoma. Further studies on IRGGs may contribute to the understanding of cancer immunity in osteosarcoma.

6897 The Role of Neutrophil Heterogeneity on T-cell Immunity in Advanced Thyroid Cancer Patients

Abstract Disclosure: Y. Kang: None. S. Lee: None. J. Yoon: None. D. Kang: None. J. Lee: None. Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I-II), and healthy controls (n=10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1+ immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T cell related pathways, such as T cell receptor signaling pathway and T cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer. Presentation: 6/3/2024

7553 Thyroid Paraganglioma: A Complex Tale of the Familiar Thyroid Nodule

Abstract Disclosure: V. Moorthy: None. A. Kondapally: None. L.E. Kimball-Ravari: None. Background: Thyroid paragangliomas are rare and often misdiagnosed on fine-needle aspiration (FNA). Clinical Case &amp; Discussion: A 58-year-old female presented with an asymptomatic “cold” thyroid nodule. Ultrasound demonstrated a 2 cm hypoechoic nodule in the isthmus. FNA yielded a follicular lesion of undetermined significance, and genomic sequencing estimated a 50% risk of malignancy prompting the patient to opt for total thyroidectomy. Histopathology and immunohistochemistry (IHC) confirmed the diagnosis of benign paraganglioma (PGL). SDH-B (succinate dehydrogenase subunit B) was notably absent on IHC. Past medical history is significant for hysterectomy for uterine fibroids and obesity, along with a confirmed family history of Hereditary Leiomyomatosis with Renal Cell Cancer (HLRCC). The patient and several family members tested positive for a pathogenic variant of fumarate hydratase (FH) gene implicated in HLRCC and undergo annual MRIs for cancer surveillance. The loss of SDH-B suggests underlying mutation. Germline SDH mutations occur in 20% of patients with pheochromocytoma and PGLs, predisposing to hereditary syndromes. PGLs are catecholamine-secreting neuroendocrine tumors with carotid body and jugular PGLs accounting for 80% of head and neck PGLs (HNPGLs). Thyroid PGLs originate from the inferior laryngeal paraganglia. They are very rare, often non-secretory, and commonly present as asymptomatic solitary nodules. For these reasons, FNA, while contraindicated, is frequently performed. If FNA is considered, pre-procedural alpha-adrenergic blockade is recommended, although catecholamine secretion triggered by FNA is uncommon. Thyroid PGLs are misdiagnosed on FNA as other thyroid neoplasms. Awareness of the more unique cytopathology of thyroid PGLs and a comprehensive IHC can aid in accurate diagnosis. Interestingly, SDH (complex 2) and FH are closely linked enzymes in the Krebs cycle. Emerging evidence correlates germline FH mutations and hereditary pheochromocytoma-paraganglioma. PGLs are less commonly associated with MEN 2A and 2B, NF type 1, VHL, and Carney-Stratakis syndrome and Carney triad. Therefore, additional testing for SDH, RET, VHL and MAX genes was recommended in this case. Total thyroidectomy or lobectomy with or without elective lymph node dissection remains the treatment of choice. Annual 24-hour urine and plasma metanephrine testing will help screen for potential recurrence. Use of GLP1 agonists for weight loss in this patient warrants further genetic and safety evaluation. Clinical Lesson/Conclusion: Often misdiagnosed on FNA, thyroid paragangliomas are rare, with multiple genetic predispositions. FNA is contraindicated and if considered, must be performed after alpha-blockade. Germline SDH mutations are implicated in PGLs and increasing evidence links FH mutations to hereditary PGLs. Presentation: 6/3/2024

Factors affecting mammogram breast cancer surveillance effectiveness in the ipsilateral and contralateral breast

AimMammography is the mainstay of imaging surveillance after breast cancer (BC) treatment, but false negatives can occur. The objective of the study was to determine the factors that can predict poorer second breast cancer (SBC) mammogram detection of the ipsilateral and contralateral breast separately. MethodsA multicentre retrospective review was performed on female patients with a previous history of treated BC who developed a second breast cancer (SBC) in the ipsilateral (ISBC) or contralateral breast (CSBC) within 10 years from the first BC. SBC cases that occurred between January 2006 and October 2017 were included from the institutional database. The ISBC and CSBC mammogram-occult (MO) rates were correlated with mammographic breast density as well as various clinical, radiological and histological characteristics of the first BC. Results274 cases of SBC were evaluated. 39.4 % (108/274) of cases were ISBC and 60.6 % (166/274) were CSBC. 35 (32.4 %) of the ISBCs and 42 (25.3 %) of the CSBCs were MO (p = 0.218). On multivariate analysis, symptomatic first BC (p = 0.041), prevailing dense breast tissue at the time of SBC diagnosis (p = 0.003) and trabecular thickening on surveillance mammograms (p = 0.017) were associated with MO ISBC. MO first BC (p < 0.001) was the only factor found to correlate with MO CSBC. ConclusionThe study found various clinical, radiological and pathological factors associated with mammogram surveillance failure for the ipsilateral and contralateral breast. This information can provide additional guidance in the planning of a personalised surveillance program using adjunct imaging screening.

Difference between sentinel and non-sentinel lymph nodes in the distribution of dendritic cells and macrophages: An immunohistochemical and morphometric study using gastric regional nodes obtained in sentinel node navigation surgery for early gastric cancer.

The sentinel lymph node (SN) concept has a significant impact on cancer surgery. We aimed to examine which morphology of dendritic cells (DCs) and macrophages corresponds to "preconditioning" of the SN against cancer. Although macrophages are generally able to tolerate cancer metastasis, the CD169-positive subtype is believed to be a limited exception. Immunohistochemical and morphometric analyses were performed to examine DC-SIGN-, CD68-, and CD169-positive cells in SNs and non-SNs of 23 patients with gastric cancer with or without nodal metastasis. All patients survived for >5 years without recurrence. DCs were present in the subcapsular, paracortical, and medullary sinuses, the endothelia of which expressed DC-SIGN and smooth muscle actin (SMA). In the non-SNs of patients without metastasis, subcapsular DCs occupied a larger area than SNs, and this difference was statistically significant. Conversely, subcapsular DCs were likely to have migrated to the paracortical area of the SNs. DC clusters often overlapped with macrophage clusters; however, histiocytosis-like clusters of CD169-negative macrophages showed a smaller overlap. We found a significantly larger overlap between DC-SIGN and CD169-positive clusters in SNs than in non-SNs; the larger overlap seemed to correspond to a higher cross-presentation of cancer antigens between these cell populations. DC-SIGN-CD169-double positive cells might exist within this overlap. SNs in gastric cancers are usually preconditioned as a frontier of cancer immunity, but they may sometimes be suppressed earlier than non-SNs. DC-SIGN- and CD169-positive cells appeared to decrease owing to a long lag time from the primary lesion occurrence and a short distance from the metastasis.

CIEC: Cross-tissue Immune Cell Type Enrichment and Expression Map Visualization for Cancer.

Single-cell transcriptome sequencing technology has been applied to decode the cell types and functional states of immune cells, revealing their tissue-specific gene expression patterns and functions in cancer immunity. Comprehensive assessments of immune cells within and across tissues will provide us with a deeper understanding of the tumor immune system in general. Here, we present Cross-tissue Immune cell type or state Enrichment analysis of gene lists for Cancer (CIEC), the first web-based application that integrates database and enrichment analysis to estimate the cross-tissue immune cell type or state. CIEC version 1.0 consists of 480 samples covering primary tumor, adjacent normal tissue, lymph node, metastasis tissue, and peripheral blood from 323 cancer patients. By applying integrative analysis, we constructed an immune cell-type/state map for each context and adopted our previously developed Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) algorithm to estimate the enrichment for context-specific immune cell type/state. In addition, CIEC also provides an easy-to-use online interface for users to comprehensively analyze the immune cell characteristics mapped across multiple tissues, including expression map, correlation, similar genes detection, signature score, and expression comparison. We believe that CIEC will be a valuable resource for exploring the intrinsic characteristics of immune cells in cancer patients and for potentially guiding novel cancer-immune biomarker development and immunotherapy strategies. CIEC is freely accessible at http://ciec.gene.ac/.

CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.

Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.

CircRNome-wide characterisation reveals the promoting role of circAATF in anti-PD-L1 immunotherapy of gallbladder carcinoma.

Circular RNAs (circRNAs) have been shown to play important roles in tumour development and tumour immunology. However, genome-wide characterisation of circRNAs and their roles in the immunology and immunotherapy of gallbladder carcinoma (GBC) has been lacking. We present a comprehensive characterisation of the circRNA landscape in GBC, revealing GBC-specific circRNAs. Our analysis found that circRNAs are significantly enriched in cell proliferation and are involved in cancer-related hallmarks. In particular, circAATF was upregulated in GBC, which was positively correlated with AATF mRNA expression, and promoted GBC cell growth. Through integrating computational and experimental approaches, we revealed that circAATF is positively associated with the CD4+ T cell abundance and PD-L1 level, and enhances the clinical benefits of anti-PD-L1 immunotherapy for GBC. We further demonstrate that circAATF elevates the PD-L1 level by activating phosphorylated AKT and acting as a sponge for miR-142-5p. CircAATF is positively associated with CD4+ T cells and PD-L1 levels and shows potential to aid anti-PD-L1 immunotherapy for GBC. Our study provides insights into roles of circAATF in the tumour development and immunology of GBC and accelerates the development of therapeutic strategies for GBC immunotherapy. HIGHLIGHTS: We present a comprehensive characterisation of circRNA landscape in gallbladder carcinoma (GBC). CircAATF is positively associated with CD4+ T cell abundance and PD-L1 expression and is shown to promote PD-L1 treatment in mouse model. CircAATF can elevate PD-L1 level through phosphorylated AKT and linear AATF, which upregulates PD-L1 by acting as a sponge of miR-142-5p.

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.

Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.

Shedding light on cancer immunology at the molecular level: A quantum biochemistry study of representative PD-1/PD-L1 conformations

BackgroundProgrammed death 1 (PD-1) binding to PD-L1 is a potent mechanism used by immunogenic tumors to evade the immune system and the immune checkpoint PD-1PD-L1 has emerged as a promising target in the search for new drugs to improve cancer treatment. The crystallographic structure of humanPD-1humanPD-L1 shed light on the molecular characterization of this system and allowed computational studies to be carried out to characterize structural behaviors. MethodsThis study demonstrated the importance of analyzing the flexibility of protein systems through molecular dynamics simulations (MDS) and its impacts on the interaction energy obtained through quantum biochemistry. ResultsThe computational results obtained provide a description of the flexibility and energetic profile of the PD-1PD-L1 contact surface using representative conformations from MDS. Variations of up to 50 % in the total interaction energy values were detected depending on the scrutinized conformation, which can be mainly attributed to the flexibility of the CC' loop, FG loop and ASP85-GLN91 of PD-1 and the MET58-LYS62 segment of PD-L1. Quantum biochemistry revealed the three hot spots in PD-L1: ARG113L-ARG125L > ILE54L-VAL76L > ALA18L-ASP26L; and two energetic hot spots in PD-1: ALA125-ARG139 > VAL63-GLN88. Nonetheless, VAL63-GLN88 and GLY124-ARG139 exhibit significant variation in interaction energy between different conformations, while ARG113L-ARG125L is the only hot spot with high energetic fluctuation on the PD-L1 surface. ConclusionThis is the first application of MDS coupled to dimensionality reduction and density functional theory (DFT) demonstrating new structural and energetic features that might be useful in discovering/designing more potent PD-1PD-L1 inhibitors.

Using Spectral Flow Cytometry to Characterize Anti-Tumor Immunity in Orthotopic and Subcutaneous Mouse Models of Cancer.

Mouse models remain at the forefront of immuno-oncology research, providing invaluable insights into the complex interactions between the immune system and developing tumors. While several flow cytometry panels have been developed to study cancer immunity in mice, most are limited in their capacity to address the complexity of anti-cancer immune responses. For example, many of the panels developed to date focus on a restricted number of leukocyte populations (T cells or antigen-presenting cells), failing to include the multitude of other subsets that participate in anti-cancer immunity. In addition, these panels were developed using blood or splenic leukocytes. While the immune composition of the blood or spleen can provide information on systemic immune responses to cancer, it is in the tumor microenvironment (TME) that local immunity takes place. Therefore, we optimized this spectral flow cytometry panel to identify the chief cell types that take part in cancer immunity using immune cells from cancer tissue. We used pancreatic tumors implanted both orthotopically and subcutaneously to demonstrate the panel's flexibility and suitability in diverse mouse models. The panel was also validated in peripheral immune districts (the blood, spleen, and liver of tumor-bearing mice) to allow comparisons between local and systemic anti-tumor immunity. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Tumor induction-Orthotopic Alternate Protocol: Tumor induction-Subcutaneous Basic Protocol 2: Preparation of single-cell suspensions from the tumor, spleen, liver, and blood of tumor-bearing mice Basic Protocol 3: Staining single-cell suspensions from the tumor, spleen, liver, and blood of tumor-bearing mice.

Targeting NQO1 induces ferroptosis and triggers anti-tumor immunity in immunotherapy-resistant KEAP1-deficient cancers

Immunotherapy has revolutionized cancer treatment, yet the efficacy of immunotherapeutic approaches remains limited. Resistance to ferroptosis is one of the reasons for the poor therapeutic outcomes in tumors with Kelch-like ECH-associated protein 1 (KEAP1) mutations. However, the specific mechanisms by which KEAP1-mutant tumors resist immunotherapy are not fully understood. In this study, we showed that the loss of function in KEAP1 results in resistance to ferroptosis. We identified NAD(P)H Quinone Dehydrogenase 1 (NQO1) as a transcriptional target of nuclear factor erythroid 2–related factor 2 (NRF2) and revealed that inducing NQO1-mediated ferroptosis in KEAP1-deficient tumors triggers an antitumor immune cascade. Additionally, it was found that NQO1 protein levels could serve as a candidate biomarker for predicting sensitivity to immunotherapy in clinical tumor patients. We validated these findings in several preclinical tumor models. Overall, KEAP1 mutations define a unique disease phenotype, and targeting its key downstream molecule NQO1 offers new hope for patients with resistance to immunotherapy.