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Open AccessArticle

Immune Pathways with Aging Characteristics Improve Immunotherapy Benefits and Drug Prediction in Human Cancer

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Cancers 2023, 15(2), 342; https://doi.org/10.3390/cancers15020342 - 04 Jan 2023

Viewed by 854

Abstract

(1) Background: Perturbation of immune-related pathways can make substantial contributions to cancer. However, whether and how the aging process affects immune-related pathways during tumorigenesis remains largely unexplored. (2) Methods: Here, we comprehensively investigated the immune-related genes and pathways among 25 cancer types using [...] Read more.

(1) Background: Perturbation of immune-related pathways can make substantial contributions to cancer. However, whether and how the aging process affects immune-related pathways during tumorigenesis remains largely unexplored. (2) Methods: Here, we comprehensively investigated the immune-related genes and pathways among 25 cancer types using genomic and transcriptomic data. (3) Results: We identified several pathways that showed aging-related characteristics in various cancers, further validated by conventional aging-related gene sets. Genomic analysis revealed high mutation burdens in cytokines and cytokines receptors pathways, which were strongly correlated with aging in diverse cancers. Moreover, immune-related pathways were found to be favorable prognostic factors in melanoma. Furthermore, the expression level of these pathways had close associations with patient response to immune checkpoint blockade therapy in melanoma and non-small cell lung cancer. Applying a net-work-based method, we predicted immune- and aging-related genes in pan-cancer and utilized these genes for potential immunotherapy drug discovery. Mapping drug target data to our top-ranked genes identified potential drug targets, FYN, JUN, and SRC. (4) Conclusions: Taken together, our systematic study helped interpret the associations among immune-related pathways, aging, and cancer and could serve as a resource for promoting clinical treatment. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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Open AccessArticle

Large-Scale Profiling of Extracellular Vesicles Identified miR-625-5p as a Novel Biomarker of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer Patients

Cancers 2022, 14(10), 2435; https://doi.org/10.3390/cancers14102435 - 14 May 2022

Cited by 7 | Viewed by 1539

Abstract

Immune checkpoint inhibitors (ICIs) are largely used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Novel biomarkers that provide biological information that could be useful for clinical management are needed. In this respect, extracellular vesicles (EV)-associated microRNAs (miRNAs) that are [...] Read more.

Immune checkpoint inhibitors (ICIs) are largely used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Novel biomarkers that provide biological information that could be useful for clinical management are needed. In this respect, extracellular vesicles (EV)-associated microRNAs (miRNAs) that are the principal vehicle of intercellular communication may be important sources of biomarkers. We analyzed the levels of 799 EV-miRNAs in the pretreatment plasma of 88 advanced NSCLC patients who received anti-PD-1 therapy as single agent. After data normalization, we used a two-step approach to identify candidate biomarkers associated to both objective response (OR) by RECIST and longer overall survival (OS). Univariate and multivariate analyses including known clinicopathologic variables and new findings were performed. In our cohort, 24/88 (27.3%) patients showed OR by RECIST. Median OS in the whole cohort was 11.5 months. In total, 196 EV-miRNAs out 799 were selected as expressed above background. After multiplicity adjustment, abundance of EV-miR-625-5p was found to be correlated with PD-L1 expression and significantly associated to OR by RECIST (p = 0.0366) and OS (p = 0.0031). In multivariate analysis, PD-L1 staining and EV-miR-625-5p levels were constantly associated to OR and OS. Finally, we showed that EV-miR-625-5p levels could discriminate patients with longer survival, in particular in the class expressing PD-L1 ≥50%. EV-miRNAs represent a source of relevant biomarkers. EV-miR-625-5p is an independent biomarker of response and survival in ICI-treated NSCLC patients, in particular in patients with PD-L1 expression ≥50%. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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Review

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Open AccessReview

Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy

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Cancers 2023, 15(11), 3009; https://doi.org/10.3390/cancers15113009 (registering DOI) - 31 May 2023

Viewed by 51

Abstract

Immunotherapy is a cancer treatment that exploits the capacity of the body’s immune system to prevent, control, and remove cancer. Immunotherapy has revolutionized cancer treatment and significantly improved patient outcomes for several tumor types. However, most patients have not benefited from such therapies [...] Read more.

Immunotherapy is a cancer treatment that exploits the capacity of the body’s immune system to prevent, control, and remove cancer. Immunotherapy has revolutionized cancer treatment and significantly improved patient outcomes for several tumor types. However, most patients have not benefited from such therapies yet. Within the field of cancer immunotherapy, an expansion of the combination strategy that targets independent cellular pathways that can work synergistically is predicted. Here, we review some consequences of tumor cell death and increased immune system engagement in the modulation of oxidative stress and ubiquitin ligase pathways. We also indicate combinations of cancer immunotherapies and immunomodulatory targets. Additionally, we discuss imaging techniques, which are crucial for monitoring tumor responses during treatment and the immunotherapy side effects. Finally, the major outstanding questions are also presented, and directions for future research are described. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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Open AccessReview

Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer

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Cancers 2023, 15(11), 2933; https://doi.org/10.3390/cancers15112933 - 26 May 2023

Viewed by 293

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Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack [...] Read more.

Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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Open AccessReview

Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment

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Carmine Valenza

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Beatrice Taurelli Salimbeni

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Cancers 2023, 15(3), 767; https://doi.org/10.3390/cancers15030767 - 26 Jan 2023

Cited by 1 | Viewed by 1045

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Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer [...] Read more.

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer treatments and derive larger benefits from immune checkpoint inhibitors. However, the assessment and the validation of TILs as a biomarker require a prospective and rigorous demonstration of its clinical validity and utility, provided reproducible analytical performance. With pending data about the prospective validation of TILs’ clinical validity to modulate treatments in early breast cancer, this review summarizes the most important current issues and future challenges related to the implementation of TILs assessments across all breast cancer subtypes and their potential integration into clinical practice. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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Open AccessReview

Turning Tertiary Lymphoid Structures (TLS) into Hot Spots: Values of TLS in Gastrointestinal Tumors

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Cancers 2023, 15(2), 367; https://doi.org/10.3390/cancers15020367 - 05 Jan 2023

Cited by 1 | Viewed by 1300

Abstract

Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregation structures found in the tumor microenvironment (TME). Emerging evidence shows that TLSs are significantly correlated with the progression of gastrointestinal tumors, patients’ prognosis, and the efficacy of adjuvant therapy. Besides, there are still some immunosuppressive [...] Read more.

Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregation structures found in the tumor microenvironment (TME). Emerging evidence shows that TLSs are significantly correlated with the progression of gastrointestinal tumors, patients’ prognosis, and the efficacy of adjuvant therapy. Besides, there are still some immunosuppressive factors in the TLSs that may affect the anti-tumor responses of TLSs, including negative regulators of anti-tumor immune responses, the immune checkpoint molecules, and inappropriate tumor metabolism. Therefore, a more comprehensive understanding of TLSs’ responses in gastrointestinal tumors is essential to fully understand how TLSs can fully exert their anti-tumor responses. In addition, targeting TLSs with immune checkpoint inhibitors and vaccines to establish mature TLSs is currently being developed to reprogram the TME, further benefiting cancer immunotherapies. This review summarizes recent findings on the formation of TLSs, the mechanisms of their anti-tumor immune responses, and the association between therapeutic strategies and TLSs, providing a novel perspective on tumor-associated TLSs in gastrointestinal tumors. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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Open AccessReview

Management of Endocrine and Metabolic Toxicities of Immune-Checkpoint Inhibitors: From Clinical Studies to a Real-Life Scenario

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Calogera Claudia Spagnolo

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Rosaria Maddalena Ruggeri

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Mariacarmela Santarpia

Cancers 2023, 15(1), 246; https://doi.org/10.3390/cancers15010246 - 30 Dec 2022

Cited by 3 | Viewed by 971

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of solid tumors. However, although ICIs are better tolerated than conventional chemotherapy, their use is associated with a peculiar toxicity profile, related to the enhancement of the immune response, affecting several organs. Among immune-related [...] Read more.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of solid tumors. However, although ICIs are better tolerated than conventional chemotherapy, their use is associated with a peculiar toxicity profile, related to the enhancement of the immune response, affecting several organs. Among immune-related adverse events (irAEs), up to 10% involve the endocrine system. Most of them are represented by thyroid disorders (hypothyroidism and hyperthyroidism), mainly correlated to the use of anti-PD-1 and/or anti-PD-L1 agents. Less common endocrine irAEs include hypophysitis, adrenalitis, and metabolic irAEs. A deeper understanding of endocrine toxicities is a critical goal for both oncologists and endocrinologists. A strict collaboration between these specialists is mandatory for early recognition and proper treatment of these patients. In this review we will provide a comprehensive overview of endocrine and metabolic adverse events of ICIs, with particular interest in the pathogenesis, predisposing factors and clinical presentation of these irAEs, and their impact on clinical outcomes of patients. Furthermore, we will summarize the most recent studies and recommendations on the clinical approach to immune-related endocrinopathies with the purpose to optimize the diagnostic algorithm, and to help both oncologists and endocrinologists to improve the therapeutic management of these unique types of irAEs, in a real-life scenario. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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Open AccessReview

Cardiotoxicity Induced by Immune Checkpoint Inhibitors: What a Cardio-Oncology Team Should Know and Do

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Concetta Zito

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Roberta Manganaro

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Giuliana Ciappina

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Calogera Claudia Spagnolo

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Vito Racanelli

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Mariacarmela Santarpia

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Nicola Silvestris

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Scipione Carerj

Cancers 2022, 14(21), 5403; https://doi.org/10.3390/cancers14215403 - 02 Nov 2022

Viewed by 1333

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic scenario for several malignancies. However, they can be responsible for immune-related adverse events (irAEs), involving several organs, with a pooled incidence ranging between 54% and 76%. The frequency of cardiovascular system involvement is <1%. Among [...] Read more.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic scenario for several malignancies. However, they can be responsible for immune-related adverse events (irAEs), involving several organs, with a pooled incidence ranging between 54% and 76%. The frequency of cardiovascular system involvement is <1%. Among the cardiovascular irAEs, myocarditis is the most common and the most dangerous but other, less common manifestations of ICI-related cardiotoxicity include pericardial disease, arrhythmias, Takotsubo-like syndrome, and acute myocardial infarction, all of which remain poorly explored. Both oncologists and cardiologists, as well as the patients, should be aware of the possible occurrence of one or more of these complications, which in some cases are fatal, in order to implement effective strategies of cardiac surveillance. In this review, we summarize the latest studies and recommendations on the pathogenesis, clinical manifestation, diagnosis, and management of ICI-related cardiotoxicity in order to realize a complete and updated overview on the main aspects of ICI-related cardiotoxicity, from surveillance to diagnosis to management, useful for both oncologists and cardiologists in their clinical practice. In particular, in the first part of the review, we realize a description of the pathogenetic mechanisms and risk factors of the main cardiovascular irAEs. Then, we focus on the management of ICI-related cardiotoxicity by analyzing five main points: (1) identifying and evaluating the type and severity of the cardiotoxicity; (2) deciding whether to withhold ICI therapy; (3) initiating steroid and immunosuppressive therapy; (4) starting conventional cardiac treatment; and (5) restarting ICI therapy. Finally, we discuss the existing evidence on surveillance for ICI-related cardiotoxicity and propose a surveillance strategy for both short- and long-term cardiotoxicity, according to the most recent guidelines. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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