Histological Origin Research Articles

Utility of expression of 4-hydroxynonenal tested by immunohistochemistry for cervical cancer.

Cervical cancer (CC) is a leading cause of mortality in women around the world, with the highest incidence rate still being in developing countries. The most common aetiological factor is infection with high-risk human papilloma virus viral strains. Oxidative stress through generation of reactive oxygen species leads to lipid peroxidation and DNA damage. Studies show that reactive lipid electrophiles such as 4-hydroxynonenal (4-HNE) produced in the process play an important role in cancer signalling pathways and are a good biomarker for oxidative stress. We aim to investigate the prognostic role of 4-HNE as a biomarker for oxidative stress in patients in early and advanced stages of CC measured by immunohistochemistry. This is a retrospective study of 69 patients treated at our Department of Oncogynaecology. Paraffin embedded tumour tissues were immunohistochemically tested for the levels of expression of 4-HNE. The results for H-score, Allred score, and combined score were investigated for association with tumour size, lymph node status, andInternational Federation of Gynaecology and Obstetrics stage. 4-hydroxynonenal showed higher expression in more advanced stages of CC and in cases with involved lymph nodes. Tumour size was not associated with the levels of 4-HNE. To best of our knowledge, this is the first study to use immunohistochemistry to examine the expression of 4-HNE as a prognostic factor in CC. The 3 score systems showed similar results. The pattern of 4-HNE histological appearance is dependent on the histological origin of cancer and is not universal.

Senescent cells in giant cell arteritis display an inflammatory phenotype participating in tissue injury via IL-6-dependent pathways

ObjectivesAge is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker...

PAEDIATRIC-06 PEDIATRIC RECURRENT PRIMARY OCCIPITAL SYNOVIAL SARCOMA: A CASE REPORT

Abstract BACKGROUND Synovial sarcoma is one of the malignant soft tissue sarcomas with an unknown histological origin. It has a unique t(X;18) (p11.2; q11.2) chromosomal translocation, resulting in the SYT-SSX fusion protein. The intracranial occurrence is mainly metastatic, and primary intracranial synovial sarcoma is extremely rare, with few case reports and case series in the literature.Surgical resection of the tumor followed by adjuvant radiotherapy and chemotherapy, regardless of the extent of tumor resection, has been shown to have a significant benefit. CASE PRESENTATION Here we report the case of an eleven-year-old male patient who presented with a four-month history of swelling at the occipital area and intermittent headache. Imaging showed a destructive skull vault lesion with infiltration of the ipsilateral cerebellum. A subtotal resection of the tumor was achieved, and histopathology examination revealed a biphasic variant of synovial sarcoma. The patient disappeared from follow-up without receiving adjuvant radiotherapy and presented two years later with a swelling at the previous surgical site. After imaging was done, a recurrence was diagnosed, and he was reoperated with near total excision. CONCLUSION Primary intracranial synovial sarcoma is an extremely rare malignant tumor. Surgical resection with adjuvant radiation should be the standard of care to prevent recurrence. In low-income countries, patients disappear from follow-up, making post-operative management difficult. Furthermore, radiation services should be made widely available to address issues with compliance.

Most Siewert type II esophagogastric junction adenocarcinomas in Chinese patients lack a Barrett esophagus background

The histological origins and classification of Siewert II esophageal gastric junction (EGJ) adenocarcinomas are controversial. While the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system suggests that they be classified as esophageal cancer, some scholars insist that these cancers include a Barrett esophageal (BE) adenocarcinoma form and a gastric adenocarcinoma form. To obtain data relevant to this debate, in this study, a multi-center sample of 25 cases of Siewert II EGJ adenocarcinoma spanning a 6-year period were analyzed. The endoscopic characteristics of the tumor lesions and pathology characteristics of peritumoral mucosal background in biopsies were determined. Cases were classified as esophageal adenocarcinoma if the tumor center was located on the oral side of the EGJ and accompanied by BE. They were classified as gastric adenocarcinoma if the tumor center was located on the anal side of the EGJ and accompanied by atrophic gastritis. Of the 25 cases examined, 20 had evaluable background mucosal data, including 14 (56 %) classified as gastric adenocarcinoma and 3 (12 %) classified as BE adenocarcinoma. The remaining 3 cases (12 %) did not have signs of BE or atrophic gastritis, and thus were not classified. Siewert type II EGJ adenocarcinoma cases in China were found to be heterogeneous, with most cases being consistent with gastric adenocarcinoma. Thus, it would not be reasonable to classify all Siewert type II EGJ adenocarcinomas as esophageal cancer.

NanoLC-MS/MS protein analysis on laser-microdissected wheat endosperm tissues: A comparison between aleurone, sub-aleurone and inner endosperm

Wheat kernel proteins are not homogeneously distributed throughout the endosperm. The goal of this study was to investigate the relative differences in protein composition between the aleurone, sub-aleurone and inner endosperm. Using laser microdissection followed by nanoLC-MS/MS, an innovative method combining high spatial specificity and analytical selectivity in sample-limited situations, 780 proteins were detected and classified by function. A higher proportion of gluten proteins was detected in the sub-aleurone than inner endosperm. Composition-wise, gluten from the sub-aleurone is relatively more enriched in ω-gliadins but impoverished in LMW-GS and γ-gliadins. While a basic set of albumins and globulins was detected in all three microdissected endosperm tissues, specific proteins, like puroindoline B, displayed a gradient. This study provides indications that both histological origin and relative positioning of the tissues drive the protein distribution. Knowledge of this protein distribution offers significant opportunities for the wheat manufacturing industry. Data available via ProteomeXchange, identifier PXD038743.

Transcriptional profiles reveal histologic origin and prognosis across 33 The Cancer Genome Atlas tumor types

Transcriptional profiles reveal histologic origin and prognosis across 33 The Cancer Genome Atlas tumor types

Immunobiology of cancer stem cells and their immunoevasion mechanisms.

Cancer stem cells (CSCs) defined as a small fraction of cells within malignancies have been isolated from tumors with different histological origins with stem related characteristics such as self-replicating potential, tumorigenesis, and therapy resistance. The dynamic communication between CSCs and tumor microenvironment particularly immune cells orchestrates their fate and plasticity as well as the patient outcome. According to recent evidence, it has been reported that they harness different immunological pathways to escape immunosurveillance and express aberrantly immunomodulatory agents or decreased levels of factors forming antigen presenting machinery (APM), subsequently followed by impaired antigen presentation and suppressed immune detection. As effective therapies are expected to be able to eradicate CSCs, mechanistic understanding of such interactions can provide insights into causes of therapy failure particularly in immunotherapy. Also, it can contribute to enhance the practical interventions against CSCs and their immunomodulatory features resulting in CSCs eradication and improving patient clinical outcome. The aim of this review is to explain the present knowledge regarding the immunobiology of CSCs and the immunoevasion mechanisms they use.

MAGE-A10 Protein Expression in Advanced High Grade Serous Ovarian Cancer Is Associated with Resistance to First-Line Platinum-Based Chemotherapy.

Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting the response to chemotherapy might help select eligible patients and spare non-responding patients from treatment-associated toxicity. Cancer/testis antigens (CTAs) are expressed by healthy germ cells and malignant cells of diverse histological origin. This expression profile identifies them as attractive targets for cancer immunotherapies. We analyzed the correlations between expression of MAGE-A10 and New York esophageal-1 cancer (NY-ESO-1) CTAs at the protein level and the effectiveness of platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). MAGE-A10 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded samples from 93 patients with advanced-stage HGSOC treated at our institutions between January 1996 and December 2013. The correlation between the expression of these markers and response to platinum-based chemotherapy, evaluated according to RECIST 1.1 criteria and platinum sensitivity, measured as platinum-free interval (PFI), progression free (PFS), and overall survival (OS) was explored. The MAGE-A10 protein expression predicted unresponsiveness to platinum-based chemotherapy (p = 0.005), poor platinum sensitivity (p < 0.001), poor PFS (p < 0.001), and OS (p < 0.001). Multivariate analysis identified MAGE-A10 protein expression as an independent predictor of poor platinum sensitivity (p = 0.005) and shorter OS (p < 0.001). Instead, no correlation was observed between the NY-ESO-1 protein expression and response to platinum-based chemotherapy (p = 0.832), platinum sensitivity (p = 0.168), PFS (p = 0.126), and OS (p = 0.335). The MAGE-A10 protein expression reliably identified advanced-stage HGSOC unresponsive to platinum-based chemotherapy. Targeted immunotherapy could represent an important alternative therapeutic option in these cancers.

Diagnostic Approaches for Neuroendocrine Neoplasms of Unknown Primary (NEN-UPs) and Their Prognostic Relevance-A Retrospective, Long-Term Single-Center Experience.

Neuroendocrine neoplasms (NENs) represent a rare and heterogenous group of tumors with predominantly gastroenteropancreatic or pulmonary origin. Despite numerous diagnostic efforts, the primary tumor site remains unknown in up to 20% of the patients diagnosed with NEN. In this subgroup of NEN patients, a standard diagnostic algorithm has not yet been integrated into clinical routine. Of note, an undetermined primary tumor site in NENs is associated with an impaired clinical outcome by at least "formally" limiting treatment options exclusively approved for NENs of a certain histological origin. In this retrospective study, a patient cohort of 113 patients initially diagnosed with NEN of unknown primary (NEN-UP) was analyzed. In 13 patients (11.5%) a primary tumor site could be identified subsequently, amongst others, by performing somatostatin receptor (SSTR)-PET-based imaging, which was irrespective of the initial clinical or demographic features. Diagnostic work-up and therapeutic regimens did not differ significantly between patients with an identified or unidentified primary tumor site; only a detailed immunohistochemical assessment providing additional information on the tumor origin proved to be significantly associated with the detection of a primary tumor site. Our study revealed that a profound diagnostic work-up, particularly including SSTR-PET-based imaging, leads to additional treatment options, finally resulting in significantly improved clinical outcomes for patients with NEN-UPs.

Advances in combined application of dental stem cells and small-molecule drugs in regenerative medicine.

Teeth are a kind of masticatory organs of special histological origin, unique to vertebrates, playing an important role in chewing, esthetics, and auxiliary pronunciation. In the past decades, with the development of tissue engineering and regenerative medicine, the studies of mesenchymal stem cells (MSCs) gradually attracted the interest of researchers. Accordingly, several types of MSCs have been successively isolated in teeth or teeth-related tissues, including dental pulp stem cells, periodontal ligament stem cells, stem cells from human exfoliated deciduous teeth, dental follicle stem cells, stem cells from apical papilla and gingival mesenchymal stem cells. These dental stem cells (DSCs) are easily accessible, possess excellent stem cell characteristics, such as high proliferation rates and profound immunomodulatory properties. Small-molecule drugs are widely used and show great advantages in clinical practice. As research progressed, small-molecule drugs are found to have various complex effects on the characteristics of DSCs, especially the enhancement of biological characteristics of DSCs, which has gradually become a hot issue in the field of DSCs research. This review summarizes the background, current status, existing problems, future research directions, and prospects of the combination of DSCs with three common small-molecule drugs: aspirin, metformin, and berberine.

The clinicopathological analysis of ocular and orbit tumors in southeast of China.

The purpose of this study is to describe the clinicopathologic characteristics of ocular surface and orbit tumors in the Southeast of China and explore the method to differentiate the benign and malignant masses. 3468 patients undergoing mass resection from January 2015 to December 2020 were selected as observation subjects and were classified into benign and malignant masses according to postoperative pathology. The clinicopathologic characteristics were collected, including gender, age, pathological tissue signs, and pathological signs. Multivariate Logistic regression analysis of independent risk factors of malignant mass was applied to establish a diagnostic model and the efficacy was evaluated by the subject working characteristics (ROC) curve. Benign tumors accounted for 91.5% of all cases, and malignant tumors accounted for 8.5%. The most common ocular benign tumors were nevi (24.2%), granuloma (17.1%), and cysts (16.4%). The most common ocular malignant tumors were malignant lymphoma (32.1%) and Basal cell carcinoma (20.2%). As for the histologic origin, melanocytic origin was on the list with 819 (23.6%), mesenchymal 661 (19.1%), epithelial 568 (16.3%), cystic 521 (15.0%), skin adnexal 110 (3.1%), lymphoid 94 (2.8%), and Neural 25(0.8%). Based on the gender, age, tumor location, and the pathological tissue image feature (including differentiation, structural atypia, covering epithelial, keratosis, nest structure/distribution, nuclear atypia, cytoplasmic change and nuclear division), the diagnostic model had predictive value to differentiate the benign and malignant masses. Most ocular surface and orbit tumors are benign. Tumor diagnosis is relative to the patient's age, gender, tumor location, and pathologic characteristics. We generated a satisfactory diagnostic model to differential diagnosis of benign and malignant masses.

Epidemiological review of multiple primary malignant neoplasms of the prostate, kidney, and bladder

Background. In recent years, an increase in the incidence of multiple primary malignancies has been observed. Multiple primary malignancies are an independent occurrence and development of two or more neoplasms of different histological origin in one patient.Aim. To evaluate epidemiological, clinical and morphological aspects of primary multiple malignant neoplasms of the prostate, kidney, and bladder.Materials and methods. Data analysis of the work report of the Saratov region oncological service in 2019, presented by the Regional Clinical Oncological Dispensary, patient case histories in the archive of the medical information system was performed.We performed a comparative analysis of the literature sources and data we obtained based to the following criteria: topographic anatomical combination of tumor locations, distribution of tumor combinations depending on time of occurrence (synchronous, metachronous), dynamics of urogenital multiple primary malignancies diagnosis in 2012-2019, distribution by gender and age, combination of stages of tumor process in both tumors, distribution by combination of histological types.Results. Between 2012 and 2019, 783 cases of multiple primary tumors with lesions in the urogenital system were identified. We studied 186 cases with a combination of two malignant neoplasms in the prostate, kidney, and bladder. Tumors developed synchronously in 36 % of patients, metachronously in 64 %. Mean patient age was 75 years. Half of the cases were in the group of localized stages - 90 (48.4 %), with the most common combination of TI-TII stages observed in 46 (24.7 %) cases. Combinations of acinar adenocarcinoma of the prostate with urothelial carcinoma of the bladder (34.7 %), clear cell renal carcinoma (27.8 %), papillary urothelial carcinoma of the bladder (12.5 %) were the most common according to histological diagnosis of primary multiple tumors of the urogenital system.Conclusion. Over the recent years we can observe a steady growth of diagnosable urogenital multiple primary malignancies. Morphological verification of the tumor and revelation of the most frequent histological types allows to assume the presence of the common mechanisms of development and the influence of tumor microenvironment on the growth of both tumors in a multiple primary malignancies pair.

A Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) for ovarian cancer

BackgroundPronectins™ are a new class of fibronectin-3-domain 14th-derived (14Fn3) antibody mimics that can be engineered as bispecific T cell engager (BTCE) to redirect immune effector cells against cancer. We describe here the in vitro and in vivo activity of a Pronectin™ AXL-targeted first-in-class bispecific T cell engager (pAXLxCD3ε) against Epithelial Ovarian Cancer (EOC).MethodspAXLxCD3ε T-cell mediated cytotoxicity was evaluated by flow cytometry and bioluminescence. pAXLxCD3ε mediated T-cell infiltration, activation and proliferation were assessed by immunofluorescence microscopy and by flow cytometry. Activity of pAXLxCD3ε was also investigated in combination with poly-ADP ribose polymerase inhibitors (PARPi). In vivo antitumor activity of pAXLxCD3ε was evaluated in immunocompromised (NSG) mice bearing intraperitoneal or subcutaneous EOC xenografts and immunologically reconstituted with human peripheral blood mononuclear cells (PBMC).ResultspAXLxCD3ε induced dose-dependent cytotoxicity by activation of T lymphocytes against EOC cells, regardless of their histologic origin. The addition of PARPi to cell cultures enhanced pAXLxCD3ε cytotoxicity. Importantly, in vivo, pAXLxCD3ε was highly effective against EOC xenografts in two different NSG mouse models, by inhibiting the growth of tumor cells in ascites and subcutaneous xenografts. This effect translated into a significantly prolonged survival of treated animals.ConclusionpAXLxCD3ε is an active therapeutics against EOC cells providing a rational for its development as a novel agent in this still incurable disease. The preclinical validation of a first-in-class agent opens the way to the development of a new 14Fn3-based scaffold platform for the generation of innovative immune therapeutics against cancer.

Immune-related mechanisms and immunotherapy in extragonadal germ cell tumors

Extragonadal germ cell tumors (EGCTs) are relatively rare tumors, accounting for 1%-5% of all GCTs. In this review, we summarize the current research progress regarding the pathogenesis, diagnosis, and treatment of EGCTs from an immunology perspective. The histological origin of EGCTs is related to a gonadal origin, but they are located outside the gonad. They show great variation in morphology and can occur in the cranium, mediastinum, sacrococcygeal bone, and other areas. The pathogenesis of EGCTs is poorly understood, and their differential diagnosis is extensive and challenging. EGCT behavior varies greatly according to patient age, histological subtype, and clinical stage. This review provides ideas for the future application of immunology in the fight against such diseases, which is a hot topic currently.

DNA Mismatch Repair System Imbalances in Breast Adenocarcinoma.

DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved system in bacteria, prokaryotic, and eukaryotic cells, and provides the highest protection to DNA by repairing micro-structural alterations. DNA MMR proteins are involved in the detection and repair of intra-nucleotide base-to-base errors inside the complementary DNA strand recognizing the recently synthesized strand from the parental template. During DNA replication, a spectrum of errors including base insertion, deletion, and miss-incorporation negatively affect the molecule's structure and its functional stability. A broad spectrum of genomic alterations such as promoter hyper methylation, mutation, and loss of heterozygosity (LOH) in MMR genes including predominantly hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 lead to their loss of base-to-base error repairing procedure. Microsatellite instability (MSI) refers to the DNA MMR gene alterations that are observed in a variety of malignancies of different histological origins. In the current review, we present the role of DNA MMR deficiency in breast adenocarcinoma, a leading cancer-based cause of death in females worldwide.

Genetic analysis and allele-specific expression of SMAD7 3′UTR variants in human colorectal cancer reveal a novel somatic variant exhibiting allelic imbalance

BackgroundConsidering the impact of SMAD7 deregulation in colorectal cancer (CRC) progression and the significance of single nucleotide variant (SNV)-mediated disruptions of microRNA (miRNA)-dependent regulation for cancer susceptibility, our study aimed to analyze genetic variation in the SMAD7 3′ untranslated region ( 3′UTR) in CRC, measure differences in allelic mRNA expression, and evaluate its interference with miRNA-mediated post-transcriptional regulation. Patients and MethodsThis study included 80 patients with different CRC stages and six human colon cancer cell lines of various histological origins. SMAD7 3′UTR was analyzed by direct sequencing, followed by the relative quantification of differential allelic expression of detected variants by allele-specific qRT-PCR. In silico tools were employed for predictions of regulatory consequences of detected variants. ResultsA total of four different SNVs in one cell line and nine patients were found, among which were a novel somatic point variant and three already known germline variants (rs16950113, rs1050799536, and rs1043778717). All evaluated SNVs exhibited variable extents of allelic imbalance in expression. In silico analysis predicted significant effects of SNVs on miRNA binding efficiency, with each SNV disrupting existing and creating new target sites for one or more miRNAs. ConclusionImbalance observed in the expression of SNV alleles altering miRNA binding suggests that all investigated SNVs are potential contributing factors impacting SMAD7 expression regulation in CRC that further studies should investigate.

Incidence of thymic malignancies in China: A longitudinal study based on a national commercial claims database from 2007 to 2016.

Incidence of thymic malignancies in China: A longitudinal study based on a national commercial claims database from 2007 to 2016.

Characteristics and transcriptomic analysis of scar tissues on the inner uterine cavity wall in patients with intrauterine adhesions.

Introduction: It has been previously reported that intrauterine adhesions (IUAs) are the main cause of uterine infertility. However, the histological origin of scar tissue present on the inner wall of the uterine cavity with IUAs has not been previously studied, which is particularly necessary for follow-up research and prevention and treatment. Methods: In this study, myometrium with normal uterus were assigned to the control group and scar tissues with IUAs were assigned to the experimental group. And pathological characteristics and transcriptomic were analyzed between the two groups. Results: We founded no difference was noted in the histological morphology and the α-SMA expression between the experimental and control groups. A total of 698 differentially expressed genes were identified between the two groups. Gene Ontology (GO) analyses revealed that the DEGs were significantly enriched in cell proliferation, AP-1 complex formation, and angiogenesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the target genes were significantly enriched in the AGE-RAGE, FOXO and TNF signaling pathway. Discussion: As far as we know, this is the first study to propose that the scar tissues are mainly derived from the myometrium and the first one to report differentially expressed genes in the scar tissues of IUAs.

Squamous-columnar junction of Von Ebner's glands may be a significant origin of squamous cell carcinomas in the base of the tongue.

The histological origin of base of the tongue (BOT) carcinomas is still elusive, and most studies have been focusing on the lingual tonsil. In this study, we sought to identify the existence of the squamous-columnar junction (SCJ) in the human Von Ebner's glandular duct and explored the potential of that in forming squamous cell carcinomas in BOT. The specific genomes of BOT carcinoma were acquired and screened out by The Cancer Genome Atlas (TCGA) database analysis. The 4-nitroquinoline-1-oxide (4-NQO)-treated mouse model was used to explore the transformation of SCJ during cancerization. We used immunohistochemistry to confirm the characteristics of SCJ in human Von Ebner's gland, which were further compared with those in the anus and cervix. The SCJ in the human Von Ebner's glandular duct was found to be similar to that of the cervix and anus. The transformation zone in the 4-NQO-treated mouse model had a multilayered epithelium structure similar to that of HPV16-transgenic mice. In human, the transformation zone of Von Ebner's gland is also similar to that of the cervix and anus. It is the first time that the existence of SCJ in the opening of the human Von Ebner's glandular duct was confirmed. The SCJ of Von Ebner's glands may be a significant origin of squamous cell carcinomas in BOT.

Abstract PR019: Mutant KRAS-specific T cell receptors directed against prevalent G12D and G12V variants exhibit potent cytotoxic activity and CD8 co-receptor independence

Abstract Background: KRAS mutations drive tumorigenesis in &amp;gt;90% of pancreatic ductal adenocarcinomas (PDAC). Recent clinical evidence demonstrates potent and durable anti-tumor activity of adoptively transferred KRAS-specific T cells in select patients with metastatic KRAS-mutated solid tumors including PDAC. We have defined mutant KRAS (mKRAS) epitopes restricted to high prevalence HLA class I alleles and validated this oncoprotein as an immunological target amenable to T cell receptor (TCR)-based therapeutic approaches. TCR therapies utilizing HLA class I-restricted TCRs often fail to harness CD4+ T cell activity vital for sustained anti-tumor immune responses. Here, we characterize HLA class I-restricted TCRs isolated from healthy donors and vaccinated patients targeting KRAS G12D or G12V, the most prevalent mKRAS variants observed in PDAC tumors. Methods: mKRAS-specific TCR sequences were identified from healthy donors or vaccinated PDAC patients enrolled on IRB-approved clinical studies at the University of Pennsylvania. Transgenic expression of synthetic TCRs was attained via lentiviral transduction of reporter cell lines or gene-edited (TCRabnull) primary CD8+ or CD4+ T cells. Limiting peptide dilution and combinatorial peptide library assays were used to assess antigen specificity, affinity and cross-reactivity. TCR reactivity to mKRAS cell lines was assessed by FACS analysis, in vitro cytotoxicity assays (4h 51Cr-release, xCELLigence Real Time Cell Analysis), and mouse xenograft tumor models. Results: TCRs exhibit specificity to the cognate KRAS G12D or G12V epitope without cross-reactivity to wild-type KRAS. TCRs are of high affinity and promote cytolysis of HLA-matched tumor cell lines harboring endogenous KRAS mutations irrespective of histologic origin. The adoptive transfer of gene-edited (TCRabnull) primary CD8+ T cells expressing synthetic TCRs exhibit potent in vivo antitumor activity in mouse xenograft tumor models of metastatic cancer. Select TCRs retain functional avidity independent of the CD8 co-receptor as determined by multimer binding and limiting peptide dilution assays. Disruption of the CD8:HLA binding interface via the introduction of D227A and T228A mutations within the HLA a3 domain has limited to no effect on TCR-mediated CD8+ T cell cytolytic activity. Transgenic expression of co-receptor independent TCRs by CD4+ T cells confers cytolytic activity against KRAS-mutated cell lines in both short- and long-term cytotoxicity assays, and flow cytometric analysis confirms antigen-specific expression of CD107a, IFN-g, TNF-a and IL-2 in a subset of CD4+ T cells. Conclusion: This study identifies TCRs with high therapeutic potency for the clinical development of TCR therapy trials targeting mKRAS in PDAC patients. Select TCRs exhibit CD8 co-receptor independence. CD4+ T cells redirected with co-receptor independent TCRs exhibit cytotoxic activity and express Th1 cytokines which may serve to enhance the persistence and anti-tumor activity of adoptive TCR therapy targeting mKRAS. Citation Format: Adham S. Bear, Rebecca B. Nadler, John Scholler, Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno. Mutant KRAS-specific T cell receptors directed against prevalent G12D and G12V variants exhibit potent cytotoxic activity and CD8 co-receptor independence [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR019.