ABSTRACT
MOTIVATION: Circulating-cell free DNA (cfDNA) is widely explored as a non-invasive biomarker for cancer screening and diagnosis. The ability to decode the cells of origin in cfDNA would provide biological insights into pathophysiological mechanisms, aiding in cancer characterization and directing clinical management and follow-up. RESULTS: We developed a DNA methylation signature-based deconvolution algorithm, MetDecode, for cancer tissue origin identification. We built a reference atlas exploiting de novo and published whole-genome methylation sequencing data for colorectal, breast, ovarian and cervical cancer, and blood-cell-derived entities. MetDecode models the contributors absent in the atlas with methylation patterns learnt on-the-fly from the input cfDNA methylation profiles. Additionally, our model accounts for the coverage of each marker region to alleviate potential sources of noise. In-silico experiments showed a limit of detection down to 2.88% of tumour tissue contribution in cfDNA. MetDecode produced Pearson correlation coefficients above 0.95 and outperformed other methods in simulations (p < 0.001; T-test; one-sided). In plasma cfDNA profiles from cancer patients, MetDecode assigned the correct tissue-of-origin in 84.2% of cases. In conclusion, MetDecode can unravel alterations in the cfDNA pool components by accurately estimating the contribution of multiple tissues, while supplied with an imperfect reference atlas. AVAILABILITY: MetDecode is available at https://github.com/JorisVermeeschLab/MetDecode. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
ABSTRACT
Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Subject(s)
Breast Neoplasms , Humans , Female , Biomarkers, Tumor/genetics , Prognosis , Phenotype , United Kingdom , Tumor MicroenvironmentABSTRACT
BACKGROUND: Several diagnostic prediction models to help clinicians discriminate between benign and malignant adnexal masses are available. This study is a head-to-head comparison of the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model with that of the Risk of Ovarian Malignancy Algorithm (ROMA). METHODS: This is a retrospective study based on prospectively included consecutive women with an adnexal tumour scheduled for surgery at five oncology centres and one non-oncology centre in four countries between 2015 and 2019. The reference standard was histology. Model performance for ADNEX and ROMA was evaluated regarding discrimination, calibration, and clinical utility. RESULTS: The primary analysis included 894 patients, of whom 434 (49%) had a malignant tumour. The area under the receiver operating characteristic curve (AUC) was 0.92 (95% CI 0.88-0.95) for ADNEX with CA125, 0.90 (0.84-0.94) for ADNEX without CA125, and 0.85 (0.80-0.89) for ROMA. ROMA, and to a lesser extent ADNEX, underestimated the risk of malignancy. Clinical utility was highest for ADNEX. ROMA had no clinical utility at decision thresholds <27%. CONCLUSIONS: ADNEX had better ability to discriminate between benign and malignant adnexal tumours and higher clinical utility than ROMA. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01698632 and NCT02847832.
Subject(s)
Adnexal Diseases , Ovarian Neoplasms , Humans , Female , Retrospective Studies , Ultrasonography , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/surgery , Ovarian Neoplasms/pathology , Adnexal Diseases/diagnosis , Adnexal Diseases/surgery , Adnexal Diseases/pathology , Algorithms , Sensitivity and Specificity , CA-125 AntigenABSTRACT
Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.
Subject(s)
Colonic Neoplasms , Humans , Biomarkers , Benchmarking , Lymphocytes, Tumor-Infiltrating , Spatial Analysis , Tumor MicroenvironmentABSTRACT
The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Subject(s)
Mammary Neoplasms, Animal , Triple Negative Breast Neoplasms , Humans , Animals , Lymphocytes, Tumor-Infiltrating , Biomarkers , Machine LearningABSTRACT
BACKGROUND: Uterine fibroids are benign monoclonal tumors originating from the smooth muscle cells of the myometrium, constituting the most prevalent pathology within the female genital tract. Uterine sarcomas, although rare, still represent a diagnostic challenge and should be managed in centers with adequate expertise in gynecological oncology. OBJECTIVES: This article is aimed to summarize and discuss cutting-edge elements about the diagnosis and management of uterine fibroids and sarcomas. METHODS: This paper is a report of the lectures presented in an expert meeting about uterine fibroids and sarcomas held in Palermo in February 2023. OUTCOME: Overall, the combination of novel molecular pathways may help combine biomarkers and expert ultrasound for the differential diagnosis of uterine fibroids and sarcomas. On the one hand, molecular and cellular maps of uterine fibroids and matched myometrium may enhance our understanding of tumor development compared to histologic analysis and whole tissue transcriptomics, and support the development of minimally invasive treatment strategies; on the other hand, ultrasound imaging allows in most of the cases a proper mapping the fibroids and to differentiate between benign and malignant lesions, which need appropriate management. CONCLUSIONS AND OUTLOOK: The choice of uterine fibroid management, including pharmacological approaches, surgical treatment, or other strategies, such as high-intensity focused ultrasound (HIFU), should be carefully considered, taking into account the characteristics of the patient and reproductive prognosis.
Subject(s)
High-Intensity Focused Ultrasound Ablation , Leiomyoma , Sarcoma , Uterine Myomectomy , Uterine Neoplasms , Female , Humans , Treatment Outcome , Leiomyoma/diagnosis , Leiomyoma/therapy , Leiomyoma/pathology , Uterine Neoplasms/diagnosis , Uterine Neoplasms/therapy , Uterine Neoplasms/pathology , Prognosis , Sarcoma/diagnosis , Sarcoma/therapy , High-Intensity Focused Ultrasound Ablation/methodsABSTRACT
BACKGROUND: Cell-free DNA (cfDNA) analysis holds great promise for non-invasive cancer screening, diagnosis, and monitoring. We hypothesized that mining the patterns of cfDNA shallow whole-genome sequencing datasets from patients with cancer could improve cancer detection. METHODS: By applying unsupervised clustering and supervised machine learning on large cfDNA shallow whole-genome sequencing datasets from healthy individuals (n = 367) and patients with different hematological (n = 238) and solid malignancies (n = 320), we identified cfDNA signatures that enabled cancer detection and typing. RESULTS: Unsupervised clustering revealed cancer type-specific sub-grouping. Classification using a supervised machine learning model yielded accuracies of 96% and 65% in discriminating hematological and solid malignancies from healthy controls, respectively. The accuracy of disease type prediction was 85% and 70% for the hematological and solid cancers, respectively. The potential utility of managing a specific cancer was demonstrated by classifying benign from invasive and borderline adnexal masses with an area under the curve of 0.87 and 0.74, respectively. CONCLUSIONS: This approach provides a generic analytical strategy for non-invasive pan-cancer detection and cancer type prediction.
Subject(s)
Cell-Free Nucleic Acids , Neoplasms , Biomarkers, Tumor/genetics , Humans , Neoplasms/diagnosis , Neoplasms/genetics , Whole Genome SequencingABSTRACT
OBJECTIVE: Ovarian cancer remains the fifth leading cause of cancer-related deaths in women. The immune system influences the onset and progression of ovarian cancer. Therefore, we aimed to study the behavior of ovarian cancer in patients with a pre-existing immune dysfunction, more specifically autoimmune disease. METHODS: For this systematic review we carried out a systematic search of four electronic databases (MEDLINE, Embase, CENTRAL, Web of Science) with the two main search terms "autoimmunity" and "ovarian cancer" up to May 10, 2020. We included 36 different autoimmune diseases in our search. From the 4799 screened records, we identified 53 relevant articles for our review, of which 48 were used in our meta-analysis. RESULTS: The incidence of ovarian cancer was significantly lower in patients with multiple sclerosis (standardized incidence ratio (SIR) 0.76, 95% CI 0.60 to 0.96). There was a tendency towards a lower risk of ovarian cancer in patients with systematic lupus erythematosus (SIR 0.89, 95% CI 0.68 to 1.15) and a tendency towards a higher risk in those with type 1 diabetes mellitus (SIR 1.49, 95% CI 0.98 to 2.28); however, this was not statistically significant. No conclusions could be drawn on mortality or the influence of immunosuppressive drugs used in the treatment of autoimmune diseases and the incidence of ovarian cancer. CONCLUSIONS: Our study showed a decreased incidence of ovarian cancer in patients with multiple sclerosis. However, further investigation on the role of the immune system in the development of ovarian cancer in women with autoimmune diseases remains necessary.
Subject(s)
Autoimmune Diseases , Multiple Sclerosis , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/epidemiology , Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , Multiple Sclerosis/epidemiologyABSTRACT
PURPOSE OF REVIEW: Uterine cancer comprises endometrial carcinoma and the uterine sarcoma. Endometrial carcinomas are the most frequent variant and have early symptoms and a solid diagnostic work up, resulting in a rather fair prognosis. However, in case of advanced stage disease and relapse, treatment options are limited and prognosis is impaired. Uterine sarcomas are rare, often lacking symptoms and no diagnostic tool for correct pre-operative diagnosis are available. Prognosis is poor. RECENT FINDINGS: Circulating biomarkers as a liquid biopsy could be beneficial as a diagnostic tool in uterine sarcomas. For both carcinomas and sarcomas, circulating biomarkers could be of use in predicting early disease recurrence. This review in endometrial carcinoma and uterine sarcoma focus on circulating biomarkers; such as proteins; circulating tumor cells; circulating tumor DNA; microRNA; and immune cells.
Subject(s)
Biomarkers, Tumor/blood , Endometrial Neoplasms/blood , Sarcoma/blood , Uterine Neoplasms/blood , Endometrial Neoplasms/pathology , Female , Humans , Liquid Biopsy , Neoplastic Cells, Circulating/pathology , Prognosis , Sarcoma/pathology , Uterine Neoplasms/diagnosis , Uterine Neoplasms/pathologyABSTRACT
BACKGROUND: Ovarian tumours are usually surgically removed because of the presumed risk of complications. Few large prospective studies on long-term follow-up of adnexal masses exist. We aimed to estimate the cumulative incidence of cyst complications and malignancy during the first 2 years of follow-up after adnexal masses have been classified as benign by use of ultrasonography. METHODS: In the international, prospective, cohort International Ovarian Tumor Analysis Phase 5 (IOTA5) study, patients aged 18 years or older with at least one adnexal mass who had been selected for surgery or conservative management after ultrasound assessment were recruited consecutively from 36 cancer and non-cancer centres in 14 countries. Follow-up of patients managed conservatively is ongoing at present. In this 2-year interim analysis, we analysed patients who were selected for conservative management of an adnexal mass judged to be benign on ultrasound on the basis of subjective assessment of ultrasound images. Conservative management included ultrasound and clinical follow-up at intervals of 3 months and 6 months, and then every 12 months thereafter. The main outcomes of this 2-year interim analysis were cumulative incidence of spontaneous resolution of the mass, torsion or cyst rupture, or borderline or invasive malignancy confirmed surgically in patients with a newly diagnosed adnexal mass. IOTA5 is registered with ClinicalTrials.gov, number NCT01698632, and the central Ethics Committee and the Belgian Federal Agency for Medicines and Health Products, number S51375/B32220095331, and is ongoing. FINDINGS: Between Jan 1, 2012, and March 1, 2015, 8519 patients were recruited to IOTA5. 3144 (37%) patients selected for conservative management were eligible for inclusion in our analysis, of whom 221 (7%) had no follow-up data and 336 (11%) were operated on before a planned follow-up scan was done. Of 2587 (82%) patients with follow-up data, 668 (26%) had a mass that was already in follow-up at recruitment, and 1919 (74%) presented with a new mass at recruitment (ie, not already in follow-up in the centre before recruitment). Median follow-up of patients with new masses was 27 months (IQR 14-38). The cumulative incidence of spontaneous resolution within 2 years of follow-up among those with a new mass at recruitment (n=1919) was 20·2% (95% CI 18·4-22·1), and of finding invasive malignancy at surgery was 0·4% (95% CI 0·1-0·6), 0·3% (<0·1-0·5) for a borderline tumour, 0·4% (0·1-0·7) for torsion, and 0·2% (<0·1-0·4) for cyst rupture. INTERPRETATION: Our results suggest that the risk of malignancy and acute complications is low if adnexal masses with benign ultrasound morphology are managed conservatively, which could be of value when counselling patients, and supports conservative management of adnexal masses classified as benign by use of ultrasound. FUNDING: Research Foundation Flanders, KU Leuven, Swedish Research Council.
Subject(s)
Adnexal Diseases/drug therapy , Diagnosis, Differential , Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Adnexal Diseases/diagnosis , Adnexal Diseases/pathology , Adnexal Diseases/surgery , Adolescent , Adult , Aged , Cohort Studies , Female , Humans , Middle Aged , Neoplasms/diagnosis , Neoplasms/pathology , Neoplasms/surgery , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Prospective Studies , Risk Factors , Ultrasonography , Young AdultABSTRACT
BACKGROUND: The behavior of the immune system as a driver in the progression of ovarian cancer has barely been studied. Our knowledge is mainly limited to the intra-tumoral adaptive immune system. Because of the widespread metastases of ovarian cancer, an assessment of the circulating immune system seems more accurate.To demonstrate the presence of immune cells in blood samples of patients with ovarian neoplasms. METHODS: In this exploratory prospective cohort study, peripheral blood mononuclear cells were collected at diagnosis from 143 women, including 62 patients with benign cysts, 13 with borderline tumor, 41 with invasive ovarian cancer, and 27 age-matched healthy controls. Immune profile analyses, based on the presence of CD4 (cluster of differentiation), CD8, natural killer cells, myeloid-derived suppressor cells, and regulatory T cells, were performed by fluorescence activated cell sorting. RESULTS: In a multivariable analysis, six immune cells (activated regulatory T cells, natural killer cells, myeloid-derived suppressor cells, monocytic myeloid-derived suppressor cells, exhausted monocytic myeloid-derived suppressor cells, and total myeloid cells) were selected as independent predictors of malignancy, with an optimism-corrected area under the receiver operating characteristic curve (AUC) of 0.858. In contrast, a profile based on CD8 and regulatory T cells, the current standard in ovarian cancer immunology, resulted in an AUC of 0.639. CONCLUSIONS: Our immune profile in blood suggests an involvement of innate immunosuppression driven by myeloid-derived suppressor cells in the development of ovarian cancer. This finding could contribute to clinical management of patients and in selection of immunotherapy.
Subject(s)
Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/pathology , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Adaptive Immunity , Adult , Case-Control Studies , Cohort Studies , Diagnosis, Differential , Female , Humans , Immunity, Innate , Ovarian Neoplasms/blood , Ovarian Neoplasms/diagnosis , Prognosis , Prospective StudiesABSTRACT
OBJECTIVE: The effect of CA125, neutrophil to lymphocyte ratio (NLR) and thrombocytosis on survival has been studied in ovarian cancer. This study explores the link between these variables and serum markers of ovarian cancer patients, such as signaling proteins and cytokines. METHODS: Serum samples of 39 patients with high-grade serous ovarian cancer (HGSOC) were collected at diagnosis and were retrospectively analysed for clinical characteristics, clinical parameters (NLR, CA125, platelet count) and immune profile [IL-4 (interleukin), IL-10, IL-13, IL-17, transforming growth factor-ß, Arginase-1, Interferon gamma), vascular endothelial growth factor (VEGF), galectin-1 and chemokine (C-C) motif ligand 2. RESULTS: CA125 correlates negatively with VEGF (pâ¯=â¯0.02) and if CA125 rises above 500â¯kU/L, IL-10 is significantly increased (pâ¯=â¯0.01). NLRâ¯>â¯6 (pâ¯<â¯0.01) was significantly correlated with decreased overall survival. Thrombocytosis was significantly correlated with IL-10 (pâ¯<â¯0.01) and a platelet countâ¯>â¯400â¯×â¯109/l led to an improvement in progression free survival (pâ¯<â¯0.01). CONCLUSIONS: A correlation, at the time of diagnosis, of HGSOC between CA125, NLR and thrombocytes and an immunosuppressive cytokine-profile in serum is shown, and correlates with survival.
Subject(s)
CA-125 Antigen/blood , Lymphocytes/metabolism , Neutrophils/metabolism , Platelet Count/methods , Disease-Free Survival , Female , Humans , Ovarian Neoplasms/blood , Ovarian Neoplasms/immunology , Retrospective StudiesABSTRACT
OBJECTIVES: A large variety of mouse models for cancer exist, also in the field of ovarian cancer. Each model possesses different features, which makes it difficult to interpret their translational value. This review provides an overview of the available ovarian cancer mouse models and their possible use in search for new treatments. METHODS: This was a PubMed search of available literature on genetically engineered mouse models, xenografts, transplantable models, and immunocompetent mouse models in ovarian cancer, with a specific focus on clinically relevant features of the described models. RESULTS/CONCLUSIONS: Several preclinical models are available for ovarian cancer. Based on their properties, a model should be carefully selected as a function of the experimental setup to achieve clinically relevant results.
Subject(s)
Neoplasms, Experimental , Ovarian Neoplasms , Animals , Female , Humans , MiceABSTRACT
STUDY QUESTION: Do sonographic characteristics of ovarian endometriomas vary with age in premenopausal women? SUMMARY ANSWER: With increasing age, multilocular cysts and cysts with papillations and other solid components become more common whereas ground glass echogenicity of cyst fluid becomes less common. WHAT IS KNOWN ALREADY: Expectant or medical management of women with endometriomas is now accepted. Therefore, the accuracy of non-invasive diagnosis of these cysts is pivotal. A clinically relevant question is whether the sonographic characteristics of ovarian endometriomas are the same irrespective of the age of the woman. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of cross-sectional data in the International Ovarian Tumor Analysis (IOTA) database. The database contains clinical and ultrasound information collected pre-operatively between 1999 and 2012 from 5914 patients with adnexal masses in 24 ultrasound centres in 10 countries. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 1005 histologically confirmed endometriomas in adult premenopausal patients found in the database and these were used in our analysis. The following ultrasound variables (defined using IOTA terminology) were used to describe the ultrasound appearance of the endometriomas: tender mass at ultrasound, largest diameter of lesion, tumour type (unilocular, unilocular-solid, multilocular, multilocular-solid, solid), echogenicity of cyst content, presence of papillations, number of papillations, height (mm) of largest papillation, presence and proportion of solid tissue and number of cyst locules, as well as vascularity in papillations and colour content of the tumour scan (colour score) on colour or power Doppler ultrasounds. Results are reported as median difference or odds ratio (OR) per 10 years increase in age. MAIN RESULTS AND THE ROLE OF CHANCE: Maximal lesion diameter did not vary substantially with age (+1.3 mm difference per 10 years increase in age, 95% confidence interval (CI) -1.4 to 4.0). Tender mass at scan was less common in the older the woman (OR 0.75, 95% CI 0.63-0.89), as were unilocular cysts relative to multilocular cysts (OR 0.70, 95% CI 0.57-0.85) and to lesions with solid components (OR 0.61, 95% CI 0.48-0.77), and ground glass echogenicity relative to homogeneous low-level echogenicity (OR 0.74, 95% CI 0.58-0.94) and other types of echogenicity of cyst contents (OR 0.64, 95% CI 0.50-0.81). Papillations were more common the older the woman (OR 1.65, 95% CI 1.24-2.21), but their height and vascularization showed no clear relation to age. LIMITATIONS, REASONS FOR CAUTION: It is a limitation that we have little clinical information on the women included, e.g. previous surgery or medical treatment for endometriosis. It is important to emphasize that we do not know the age of the endometrioma itself and that our study is not longitudinal and so does not describe changes in endometriomas over time. The differences in the ultrasound appearance of endometriomas between women of different ages might be explained by previous surgery or medical treatment and might not be an effect of age per se. WIDER IMPLICATIONS OF THE FINDINGS: Awareness of physicians that the ultrasound appearance of endometriomas differs between women of different ages may facilitate a correct diagnosis of endometrioma. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by the Regione Autonoma della Sardegna (project code CPR-24750). B.V.C., A.C. and D.T. are supported by the Fund for Scientific Research Flanders, Belgium (FWO). The authors declare that there is no conflict of interest.
Subject(s)
Endometriosis/diagnostic imaging , Ovarian Cysts/diagnostic imaging , Ovarian Diseases/diagnostic imaging , Ultrasonography , Adolescent , Adult , Age Factors , Cross-Sectional Studies , Female , Humans , Middle Aged , Young AdultABSTRACT
Glioblastoma (GBM) is the deadliest of all brain cancers. GBM patients receive an intensive treatment schedule consisting of surgery, radiotherapy and chemotherapy, which only modestly extends patient survival. Therefore, preclinical studies are testing novel experimental treatments. In such preclinical studies, these treatments are administered as monotherapy in the majority of cases; conversely, in patients the new treatments are always combined with the standard of care. Most likely, this difference contributes to the failure of clinical trials despite the successes of the preclinical studies. In this methodological study, we show in detail how to implement the full clinical standard of care in preclinical GBM research. Systematically testing new treatments, including cellular immunotherapies, in combination with the clinical standard of care can result in a better translation of preclinical results to the clinic and ultimately increase patient survival.
Subject(s)
Brain Neoplasms , Glioblastoma , Animals , Mice , Humans , Glioblastoma/drug therapy , Temozolomide/therapeutic use , Standard of Care , Brain Neoplasms/drug therapyABSTRACT
Immune checkpoint inhibitor (ICI) therapy has proven revolutionary in the treatment of some cancers. However, ovarian cancer remains unresponsive to current leading ICIs, such as anti-PD1 or anti-PD-L1. In this article, we explored the potential of an upcoming checkpoint molecule, T-cell immunoglobulin and mucin domain 3 (TIM3), for the treatment of ovarian cancer using a syngeneic orthotopic mouse model (ID8-fLuc). Besides therapeutic efficacy, we focused on exploring immune changes in tumor tissue and peritoneal fluid. Our results showed no improvement in survival in ovarian cancer-bearing mice after anti-TIM3 treatment when used as monotherapy nor when combined with anti-PD1 or standard-of-care chemotherapy (carboplatin/paclitaxel). This was reflected in the unaltered immune infiltration in treated mice compared to control mice. Altering the order of drug administration within the combination treatment altered the survival results, but did not result in a survival benefit over chemotherapy alone. These findings highlight the need for further preclinical studies to find beneficial treatment schemes and combination therapies for ovarian cancer.
ABSTRACT
Background: Ovarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models. Methods: A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed. Results: The nature of TTFields-drug interaction was dependent on the drug's underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control. Conclusion: By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.
ABSTRACT
PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICIs) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial and functional assays to characterize the differential impact of neo-adjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to NACT-naïve HGSOC samples from 5 independent patient cohorts. RESULTS: We found neo-adjuvant chemotherapy (NACT)-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD-1+ CD8+ T cells over their ICI-insensitive TIM-3+PD-1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD-1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSION: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC.
ABSTRACT
Immune checkpoint inhibitors (ICI) have been revolutionary in the field of cancer therapy. However, their success is limited to specific indications and cancer types. Recently, the combination treatment of ICI and chemotherapy has gained more attention to overcome this limitation. Unfortunately, many clinical trials testing these combinations have provided limited success. This can partly be attributed to an inadequate choice of preclinical models and the lack of scientific rationale to select the most effective immune-oncological combination. In this review, we have analyzed the existing preclinical evidence on this topic, which is only limitedly available. Furthermore, this preclinical data indicates that besides the selection of a specific drug and dose, also the sequence or order of the combination treatment influences the study outcome. Therefore, we conclude that the success of clinical combination trials could be enhanced by improving the preclinical set up, in order to identify the optimal treatment combination and schedule to enhance the anti-tumor immunity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Immunotherapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immune Checkpoint Inhibitors , Medical Oncology , ResearchABSTRACT
The lethality of patients with ovarian cancer (OC) remains high. Current treatment strategies often do not lead to the desired outcome due to the development of therapy resistance, resulting in high relapse rates. Additionally, clinical trials testing immunotherapy against OC have failed to reach significant results to date. The OC tumor microenvironment and specifically myeloid-derived suppressor cells (MDSC) are known to generate immunosuppression and inhibit the anti-tumor immune response following immunotherapy treatment. Our review aims to characterize potential candidate treatments to target MDSC in OC through drug-repurposing. A literature search identified repurposable compounds with evidence of their suppressing the effect of MDSC. A total of seventeen compounds were withheld, of which four were considered the most promising. Lurbinectedin, metformin, celecoxib, and 5-azacytidine have reported preclinical effects on MDSC and clinical evidence in OC. They have all been approved for a different indication, characterizing them as the most promising candidates for repurposing to treat patients with OC.