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Breaking through the Barricades: Immune Checkpoint Molecules and Immunotherapy in Cancer

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 8123

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Special Issue Editor

Dr. Eva Andreuzzi

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Guest Editor

Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
Interests: tumor microenvironment; ECM; angiogenesis; drug efficacy; tumor-associated inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will focus on emerging trends in immune checkpoint molecules and immunotherapy in cancer. In recent years, the employment of immune checkpoint inhibitors (ICIs) in the treatment of several cancer types has been a clinical breakthrough that led to a significant improvement of patient outcome. The use of ICIs as single agents or in combination with conventional tumor therapy and targeted therapy is now in focus as a means to draw new therapeutic strategies that may improve clinical response and overcome the occurrence of resistance mechanisms. However, although the use of PD-1/PD-L1 and CTLA-4 inhibitors yields unprecedented clinical effects, a consistent number of patients seem not to benefit from the use of ICIs. Further studies are needed to improve our knowledge of such immunomodulatory proteins and their impact on mechanisms influencing the therapeutic response. The role of ICIs in the modulation of the crosstalk between cancer cells and other tumor-associated cell types (e.g., immune and vascular cells) is another key feature that still has not been deeply investigated. The discovery of these mechanisms has the potential to give rise to the development of new therapeutic strategies, and to the development of new prognostic and predictive biomarkers.

This Special Issue invites submissions in any area relating to these themes. Possible topics within this scope include (but are not limited to) the following:

Identification of novel immune checkpoints and inhibitors;
Molecular mechanisms regulating immune checkpoint molecule expression;
Mechanisms of resistance to ICIs;
Strategies to improve the efficacy of ICIs;
Impact of ICIs on tumor angiogenesis and lymphangiogenesis;
Mechanisms of tumor cell invasion and metastatic dissemination;
Evaluation of new biomarkers with predictive value for ICI therapies.

Dr. Eva Andreuzzi
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

immune checkpoint
ICI
cancer immunotherapy

Published Papers (4 papers)

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Research

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12 pages, 1739 KiB

Open AccessArticle

Prognostic Significance of PD-L1 Expression in Gastric Cancer Patients with Peritoneal Metastasis

by Xiao-Jiang Chen, Cheng-Zhi Wei, Jun Lin, Ruo-Peng Zhang, Guo-Ming Chen, Yuan-Fang Li, Run-Cong Nie and Yong-Ming Chen

Biomedicines 2023, 11(7), 2003; https://doi.org/10.3390/biomedicines11072003 - 15 Jul 2023

Cited by 2 | Viewed by 1648

Abstract

Background: Recently, many studies have explored the relationship between the expression of programmed death ligand 1 (PD-L1) and prognosis in gastric cancer, but there is still controversy. Additionally, few studies have specifically investigated the expression of PD-L1 in patients with peritoneal metastasis. Methods: Immunohistochemistry was used to analyze the expression of PD-L1 in gastric cancer patients with peritoneal metastasis. The combined positive score (CPS) was calculated to evaluate the expression of PD-L1, and the clinicopathological data were analyzed to explore prognostic significance. Results: In total, 147 gastric cancer patients with peritoneal metastasis were enrolled. The negative PD-L1 expression was defined as a CPS < 1, and high PD-L1 expression was defined as a CPS ≥ 10. PD-L1 expression with CPS ≥ 1 and CPS-negative was detected in 67 (45.58%) and 80 (54.42%) patients, respectively. High PD-L1 expression at PD-L1 CPS ≥ 10 was detected in 21(14.29%) patients. The median overall survival (OS) was 18.53 months in the CPS < 10 group and 27.00 months in the CPS ≥ 10 group; the OS difference between the two groups was significant (p = 0.015). Multivariate analysis demonstrated that a poor Eastern Cooperative Oncology Group performance score (ECOG PS) (p = 0.002) and severe peritoneal metastasis (p = 0.033) were significantly associated with poor survival, while palliative chemotherapy (p = 0.002) and high PD-L1 expression (p = 0.008) were independent and significantly favorable prognostic factors. Conclusions: Our study demonstrated that PD-L1 expression was widely presented in gastric cancer patients with peritoneal metastasis, while a CPS no less than 10 predicted better prognosis. Full article

(This article belongs to the Special Issue Breaking through the Barricades: Immune Checkpoint Molecules and Immunotherapy in Cancer)

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15 pages, 2294 KiB

Open AccessArticle

Prognostic Impact of LAG-3 mRNA Expression in Early Breast Cancer

by Anne-Sophie Heimes, Katrin Almstedt, Slavomir Krajnak, Anne Runkel, Annika Droste, Roxana Schwab, Kathrin Stewen, Antje Lebrecht, Marco J. Battista, Walburgis Brenner, Annette Hasenburg, Mathias Gehrmann, Jan G. Hengstler and Marcus Schmidt

Biomedicines 2022, 10(10), 2656; https://doi.org/10.3390/biomedicines10102656 - 21 Oct 2022

Cited by 3 | Viewed by 1668

Abstract

Background: Monoclonal antibodies against PD-1 or PD-L1 have been established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4), additional ICPs, such as lymphocyte activation gene-3 (LAG-3), are subject of current research. In the present retrospective gene-expression analysis, we evaluated the prognostic significance of LAG-3 in 461 patients with early breast cancer. In addition, we examined whether there was a correlation between the different ICP and CD8 expressions. Methods: Using microarray-based gene-expression analysis, we examined the prognostic significance of LAG-3 mRNA expression for metastasis-free survival (MFS) in the whole cohort of 461 breast cancer patients and among different molecular subtypes. Correlations were analyzed using Spearman’s rho correlation coefficient. Results: In the whole cohort, LAG-3 expression had no significant impact on MFS (p = 0.712, log-rank). In the subgroup analyses, there was a trend that a higher LAG-3 expression was associated with a favorable outcome in the luminal B (p = 0.217), basal-like (p = 0.370) and HER2 (p = 0.089) subtypes, although significance was not reached. In contrast, in a multivariate Cox regression analysis, adjusted for age, tumor size, axillary nodal status, histological grade of differentiation and proliferation marker Ki-67, LAG-3 showed a significant influence on MFS (HR 0.574; 95% CI 0.369–0.894; p = 0.014). High LAG-3 significantly correlated with CD8 (ρ = 0.571; p < 0.001). Conclusions: LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints, such as LAG-3, could serve as therapeutic targets in breast cancer. Full article

(This article belongs to the Special Issue Breaking through the Barricades: Immune Checkpoint Molecules and Immunotherapy in Cancer)

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11 pages, 1781 KiB

Open AccessArticle

Imaging Effector Memory T-Cells Predicts Response to PD1-Chemotherapy Combinations in Colon Cancer

by Julian L. Goggi, Shivashankar Khanapur, Siddesh V. Hartimath, Boominathan Ramasamy, Peter Cheng, Hui-Xian Chin, Jun-Rong Tang, You-Yi Hwang and Edward G. Robins

Biomedicines 2022, 10(10), 2343; https://doi.org/10.3390/biomedicines10102343 - 20 Sep 2022

Cited by 2 | Viewed by 1447

Abstract

Often, patients fail to respond to immune checkpoint inhibitor (ICI) treatment despite favourable biomarker status. Numerous chemotherapeutic agents have been shown to promote tumour immunogenicity when used in conjunction with ICIs; however, little is known about whether such combination therapies lead to a lasting immune response. Given the potential toxicity of ICI–chemotherapy combinations, identification of biomarkers that accurately predict how individuals respond to specific treatment combinations and whether these responses will be long lasting is of paramount importance. In this study, we explored [¹⁸F]AlF-NOTA-KCNA3P, a peptide radiopharmaceutical that targets the Kv1.3 potassium channel overexpressed on T-effector memory (T_EM) cells as a PET imaging biomarker for lasting immunological memory response. The first-line colon cancer chemotherapies oxaliplatin and 5-fluorouracil were assessed in a syngeneic colon cancer model, either as monotherapies or in combination with PD1, comparing radiopharmaceutical uptake to memory-associated immune cells in the tumour. [¹⁸F]AlF-NOTA-KCNA3P reliably separated tumours with immunological memory responses from non-responding tumours and could be used to measure Kv1.3-expressing T_EM cells responsible for durable immunological memory response to combination therapy in vivo. Full article

(This article belongs to the Special Issue Breaking through the Barricades: Immune Checkpoint Molecules and Immunotherapy in Cancer)

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Review

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32 pages, 1694 KiB

Open AccessReview

Breaking through Multiple Myeloma: A Paradigm for a Comprehensive Tumor Ecosystem Targeting

by Antonio G. Solimando, Markus Krebs, Vanessa Desantis, Donatello Marziliano, Ingrid Catalina Caradonna, Arcangelo Morizio, Antonella Argentiero, Endrit Shahini and Max Bittrich

Biomedicines 2023, 11(7), 2087; https://doi.org/10.3390/biomedicines11072087 - 24 Jul 2023

Cited by 1 | Viewed by 2637

Abstract

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment. Full article

(This article belongs to the Special Issue Breaking through the Barricades: Immune Checkpoint Molecules and Immunotherapy in Cancer)

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