The neoepitope landscape of breast cancer: implications for immunotherapy.
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ABSTRACT:
SUBMITTER: Narang P
PROVIDER: S-EPMC6399957 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNeoepitopes derived from tumor-specific somatic mutations are promising targets for immunotherapy in childhood cancers. However, the potential for such therapies in targeting these epitopes remains uncertain due to a lack of knowledge of the neoepitope landscape in childhood cancer. Studies to date have focused primarily on missense mutations without exploring gene fusions, which are a major class of oncogenic drivers in pediatric cancer.MethodsWe developed an analytical workflow for identification of putative neoepitopes based on somatic missense mutations and gene fusions using whole-genome sequencing data. Transcriptome sequencing data were incorporated to interrogate the expression status of the neoepitopes.ResultsWe present the neoepitope landscape of somatic alterations including missense mutations and oncogenic gene fusions identified in 540 childhood cancer genomes and transcriptomes representing 23 cancer subtypes. We found that 88% of leukemias, 78% of central nervous system tumors, and 90% of solid tumors had at least one predicted neoepitope. Mutation hotspots in KRAS and histone H3 genes encode potential epitopes in multiple patients. Additionally, the ETV6-RUNX1 fusion was found to encode putative neoepitopes in a high proportion (69.6%) of the pediatric leukemia harboring this fusion.ConclusionsOur study presents a comprehensive repertoire of potential neoepitopes in childhood cancers, and will facilitate the development of immunotherapeutic approaches designed to exploit them. The source code of the workflow is available at GitHub ( https://github.com/zhanglabstjude/neoepitope ).
| S-EPMC5577668 | biostudies-literature
Project description:ImportanceThere is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing at the time of this narrative review. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease.ObservationsAfter searching ClinicalTrials.gov on April 24, 2018, and PubMed up to June 30, 2018, to identify breast cancer immunotherapy trials, we found that immune checkpoint blockade (ICB) is the most investigated form of immunotherapy in breast cancer. Use of ICB as monotherapy has achieved objective responses in patients with breast cancer, with higher rates seen when administered in earlier lines of therapy. For responding patients, those responses are durable. More recent data suggest clinical efficacy when ICB is given in combination with chemotherapy. Ongoing studies are evaluating combination strategies pairing ICB with additional chemotherapeutic agents, targeted therapy, vaccines, and local ablative therapies to enhance response. To date, robust predictive biomarkers for response to ICB have not been established.Conclusions and relevanceIt is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions. Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors.
| S-EPMC8452050 | biostudies-literature
Project description:Necroptosis plays a major role in breast cancer (BC) progression and metastasis. Besides, necroptosis also regulates inflammatory response and tumor microenvironment. Here, we aim to explore the predictive signature based on necroptosis-related genes (NRGs) for predicting the prognosis and response to therapies. Using Lasso multivariate cox analysis, we firstly established the NRG signature based on TCGA database. A total of 6 NRGs (FASLG, IPMK, FLT3, SLC39A7, HSP90AA1, and LEF1), which were associated with the prognosis of BC patients, were selected to establish our signature. Next, CIBERSORT algorithm was utilized to evaluate immune cell infiltration levels. We compare the response to immunotherapy using IMvigor 210 database, and also compared immune indicators in two risk groups via multiple methods. The biological function of IPMK was explored via in vitro verification. Finally, our results indicated that the signature was an independent prognostic indicator for BC patients with better efficiency than other reported signatures. The immune cell infiltration levels were higher, and the response to immunotherapy and chemotherapy was better in the low-risk groups. Besides, other immunotherapy-related factors, including TMB, TIDE, and expression of immune checkpoints were also increased in the low-risk group. Clinical sample validation showed that CD206 and IPMK in clinical samples were both up-regulated in the high-risk group. In vitro assay showed that IPMK promoted BC cell proliferation and migration, and also enhanced macrophage infiltration and M2 polarization. In summary, we successfully established the NRG signature, which could be used to evaluate BC prognosis and identify patients who will benefit from immunotherapy.
| S-EPMC9306193 | biostudies-literature
Project description:Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.
| S-EPMC8657247 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) deeply changed the treatment landscape of breast cancer (BC). In particular, anti-programmed-death (ligand) 1 antibodies were approved for the treatment of triple-negative breast cancer (TNBC), both in first line for metastatic disease and in neoadjuvant setting, on the basis of a demonstrated improvement of the survival outcomes. In light of these results, current clinical trials aim at improving this benefit investigating novel combinations and strategies, at exploring the role of ICIs beyond TNBC, and at better selecting the patients in order to spare non-responders from avoidable toxicities. This narrative review aims at summarizing and discussing the evolving landscape of immunotherapeutic treatments for BC, highlighting the current challenges and the future perspectives.
| S-EPMC9893403 | biostudies-literature
Project description:IntroductionThis study aims to present the landscape of the intratumoral microenvironment and by which establish a classification system that can be used to predict the prognosis of bladder cancer patients and their response to anti-PD-L1 immunotherapy.MethodsThe expression profiles of 1554 bladder cancer cases were downloaded from seven public datasets. Single-sample gene set enrichment analysis (ssGSEA), univariate Cox regression analysis, and meta-analysis were employed to establish the bladder cancer immune prognostic index (BCIPI). Extensive analyses were executed to investigate the association between BCIPI and overall survival, tumor-infiltrated immunocytes, immunotherapeutic response, mutation load, etc.ResultsThe results obtained from seven independent cohorts and meta-analyses suggested that the BCIPI is an effective classification system for estimating bladder cancer patients' overall survival. Patients in the BCIPI-High subgroup revealed different immunophenotypic outcomes from those in the BCIPI-Low subgroup regarding tumor-infiltrated immunocytes and mutated genes. Subsequent analysis suggested that patients in the BCIPI-High subgroup were more sensitive to anti-PD-L1 immunotherapy than those in the BCIPI-Low subgroup.ConclusionsThe newly established BCIPI is a valuable tool for predicting overall survival outcomes and immunotherapeutic responses in patients with bladder cancer.
| S-EPMC9730156 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer that represents 15-20% of breast tumors and is more prevalent in young pre-menopausal women. It is the subtype of breast cancers with the highest metastatic potential and recurrence at the first 5 years after diagnosis. In addition, mortality increases when a complete pathological response is not achieved. As TNBC cells lack estrogen, progesterone, and HER2 receptors, patients do not respond well to hormone and anti-HER2 therapies, and conventional chemotherapy remains the standard treatment. Despite efforts to develop targeted therapies, this disease continues to have a high unmet medical need, and there is an urgent demand for customized diagnosis and therapeutics. As immunotherapy is changing the paradigm of anticancer treatment, it arises as an alternative treatment for TNBC patients. TNBC is classified as an immunogenic subtype of breast cancer due to its high levels of tumor mutational burden and presence of immune cell infiltrates. This review addresses the implications of these characteristics for the diagnosis, treatment, and prognosis of the disease. Herein, the role of immune gene signatures and tumor-infiltrating lymphocytes as biomarkers in TNBC is reviewed, identifying their application in patient diagnosis and stratification, as well as predictors of efficacy. The expression of PD-L1 expression is already considered to be predictive of response to checkpoint inhibitor therapy, but the challenges regarding its value as biomarker are described. Moreover, the rationales for different formats of immunotherapy against TNBC currently under clinical research are discussed, and major clinical trials are highlighted. Immune checkpoint inhibitors have demonstrated clinical benefit, particularly in early-stage tumors and when administered in combination with chemotherapy, with several regimens approved by the regulatory authorities. The success of antibody-drug conjugates and research on other emerging approaches, such as vaccines and cell therapies, will also be addressed. These advances give hope on the development of personalized, more effective, and safe treatments, which will improve the survival and quality of life of patients with TNBC.
| S-EPMC9437219 | biostudies-literature
Project description:Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies.
| S-EPMC8199088 | biostudies-literature
Project description:Although the vast majority of patients with papillary thyroid cancer (PTC) have a favorable prognosis when conventional treatments are implemented, local recurrence and distant metastasis of advanced PTCs still hamper the survival and clinical management in certain patients. As immune checkpoint blockade (ICB) therapy achieves a great success in some advanced cancers, we aimed to investigate the immune landscape in PTC and its potential implications for prognosis and immunotherapy. In this study, different algorithms were conducted to estimate immune infiltration in PTC samples. A series of bioinformatic and machine learning approaches were performed to identify PTC-specific immune-related genes (IRGs) and distinct immune clusters. Differences in intrinsic tumor immunogenicity and potential immunotherapy response were observed between distinct immune clusters. A prognostic immune-related signature (IRS) was established to predict progression-free survival (PFS). IRS exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. Furthermore, an integrated survival decision tree and a scoring nomogram were constructed to improve prognostic stratification and predictive accuracy for individual patients. In addition, altered pathways, mutational patterns, and potential applicable drugs were analyzed in different immune-related risk groups. Our study gained some insight into the immune landscape of PTC, and provided some useful clues for introducing immune-based molecular classification into risk stratification and guiding ICB decision-making.
| S-EPMC8425706 | biostudies-literature
Project description:Although unlikely to replace current standard of care therapies, immunotherapy is emerging as a critical component of breast cancer treatment. Despite initial setbacks, clinical benefit is now evident through immunomodulation and cancer vaccines. Over the past decade, passive immunotherapeutic strategies such as anti-HER2 monoclonal antibody (mAb) therapy have significantly improved the prognosis in HER2 overexpressing breast cancers. Novel active immunotherapeutic strategies include checkpoint blockade modifiers, also a mAb therapy. Although non-specific, checkpoint blockade modifiers show great promise in clinical trials. A form of active and specific immunotherapy, cancer vaccines may be used alone or in conjunction with these aforementioned mAb therapies. While there is significant initial promise, the complexities of the host immune system-tumor interaction and the vast array of potential immune targets require the field of cancer immunotherapy to be further developed. Here, we briefly discuss the field of breast immunotherapy to date and its implications for the future of breast cancer care.
| S-EPMC5327815 | biostudies-literature