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3 pages, 189 KiB

Open AccessEditorial

Current Landscape and Future Direction of PD-1/PD-L1 Checkpoint Inhibitors in Cancer Treatment

by Simona Serratì and Francesca Margheri

Biomolecules 2023, 13(8), 1209; https://doi.org/10.3390/biom13081209 - 1 Aug 2023

Cited by 2 | Viewed by 1992

Abstract

Immune checkpoints are involved in controlling the activation or inhibition of the immune response and are associated with receptors on the immune cell surface [...] Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

Research

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15 pages, 2264 KiB

Open AccessArticle

Germline PDCDL1 Gene Variants Are Associated with Increased Primary Melanoma Thickness

by Elizabeth Córdoba-Lanús, Omar García-Pérez, Leticia Melgar-Vilaplana, Angélica Domínguez-de-Barros and Ricardo Fernández-de-Misa

Biomolecules 2025, 15(4), 584; https://doi.org/10.3390/biom15040584 - 15 Apr 2025

Viewed by 203

Abstract

Background: The incidence of malignant melanoma (MM) continues to increase annually, and tumour invasiveness is a main prognostic factor. Single-nucleotide polymorphisms (SNPs) have become key tools in the study of cancer genetics, influencing susceptibility and prognosis. Methods: In the present study, [...] Read more.

Background: The incidence of malignant melanoma (MM) continues to increase annually, and tumour invasiveness is a main prognostic factor. Single-nucleotide polymorphisms (SNPs) have become key tools in the study of cancer genetics, influencing susceptibility and prognosis. Methods: In the present study, we analysed the relationship between five SNPs on the PDCDL1 gene (rs822336, rs822337, rs822338, rs229736, rs4143815) with prognosis as well as primary tumour invasiveness characteristics in 377 whole blood samples from MM individuals. Results: Patients who presented the rs822336 CG or GG genotypes (OR = 3.01, 95% CI = 1.53–5.92; p = 0.0017), TA or TT in rs822337 (OR = 2.45, 95% CI = 1.22–4.93; p = 0.0098), and CT or CC of rs822338 (OR = 2.23, 95% CI = 1.05–4.73; p = 0.028) were at an increased risk of developing invasive melanomas. Cases with the AG or GG genotype in rs2297136 presented a lower risk (OR = 0.29, 95% CI = 0.11–0.75; p = 0.0038) of invasive MM. The genetic analysis at the haplotype level resulted in similar findings (OR: 2.95, 95% CI: 1.08–8.10), p = 0.036). Furthermore, patients carrying the homozygous AA genotype in rs2297136 had thicker tumours than those harbouring the AG or GG (1.4 mm vs. 1.0 and 0.8 mm; p = 0.030). No significant association was found between the studied SNPs and melanoma-specific survival (MSS) nor progression-free survival (PFS). Conclusions: Current results suggest that SNPs rs822336, rs822337, rs822338, and rs2297136 genotypes in the PDCDL1 gene are associated with the risk of tumour invasiveness and tumour thickness in MM. Further studies on SNPs considering genetic and epigenetic factors are needed for a better understanding of malignant melanoma susceptibility and its prognosis. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

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16 pages, 1110 KiB

Open AccessArticle

by Sonja Cotra, Mohammad Kohandel and Michelle Przedborski

Biomolecules 2024, 14(12), 1513; https://doi.org/10.3390/biom14121513 - 27 Nov 2024

Viewed by 966

Abstract

Immune checkpoint inhibitors, such as anti-PD-1 antibodies, represent a significant advancement in cancer immunotherapy, but their efficacy varies notably between individuals, influenced by complex biological systems. Recent evidence suggests that sex-related biological differences play a pivotal role in modulating these responses. This study [...] Read more.

Immune checkpoint inhibitors, such as anti-PD-1 antibodies, represent a significant advancement in cancer immunotherapy, but their efficacy varies notably between individuals, influenced by complex biological systems. Recent evidence suggests that sex-related biological differences play a pivotal role in modulating these responses. This study uses a systems biology approach to examine how sex-specific differences in the immune system contribute to variability in the response to treatment. Our model extends previous frameworks by incorporating sex-specific parameters that reflect observed immunological distinctions. The results from the simulation studies align with our clinical observations, showing that on average, males exhibit a more robust response to anti-PD-1 treatment compared to females. Additionally, this study explores the potential of combination therapy with recombinant IL-12, revealing sex-specific differences in treatment efficacy. These findings underscore the need for personalized immunotherapy strategies that consider individual immunological profiles, including sex, to optimize treatment outcomes. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

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10 pages, 2117 KiB

Open AccessArticle

A Spatial Transcriptome Reveals Changes in Tumor and Tumor Microenvironment in Oral Cancer with Acquired Resistance to Immunotherapy

by Yoh-ichiro Iwasa, Tomoyuki Nakajima, Kentaro Hori, Yoh Yokota, Ryosuke Kitoh, Takeshi Uehara and Yutaka Takumi

Biomolecules 2023, 13(12), 1685; https://doi.org/10.3390/biom13121685 - 22 Nov 2023

Cited by 5 | Viewed by 2881

Abstract

Although anti-programmed death-1 (PD-1) antibody therapy improves the prognosis in patients with head and neck squamous cell carcinoma (HNSCC), some patients exhibit disease progression even after showing a good response to the treatment initially because of acquired resistance. Here, we aimed to reveal [...] Read more.

Although anti-programmed death-1 (PD-1) antibody therapy improves the prognosis in patients with head and neck squamous cell carcinoma (HNSCC), some patients exhibit disease progression even after showing a good response to the treatment initially because of acquired resistance. Here, we aimed to reveal the dynamic changes in the tumor and tumor microenvironment (TME) in a 77-year-old man diagnosed with oral squamous cell carcinoma who developed acquired resistance after the administration of nivolumab using spatial transcriptomics. The results showed that, before immunotherapy, the activated pathways in the tumor area were mainly related to the cancer immune system, including antigen processing cross-presentation, interferon–gamma signaling, and the innate immune system. After immunotherapy, the activated pathways were mainly related to epigenetic modification, including RMTs methylate histone arginine and HDAC deacetylates histones. Before immunotherapy, the activated pathways in the TME were mainly related to the metabolism of proteins, including SRP-dependent co-translational protein targeting the membrane. After immunotherapy, the activated pathways in the TME were related to sensory perception and signal transduction. Our study revealed that epigenetic-modification-related pathways were mainly activated after establishing acquired resistance, suggesting that epigenetic modification in the tumor may prevent cancer immune system activation via the anti-PD-1 antibody. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

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Review

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12 pages, 1002 KiB

Open AccessReview

Optimizing Immunotherapy: The Synergy of Immune Checkpoint Inhibitors with Artificial Intelligence in Melanoma Treatment

by Mohammad Saleem, Abigail E. Watson, Aisha Anwaar, Ahmad Omar Jasser and Nabiha Yusuf

Biomolecules 2025, 15(4), 589; https://doi.org/10.3390/biom15040589 - 16 Apr 2025

Viewed by 332

Abstract

Immune checkpoint inhibitors (ICIs) have transformed melanoma treatment; however, predicting patient responses remains a significant challenge. This study reviews the potential of artificial intelligence (AI) to optimize ICI therapy in melanoma by integrating various diagnostic tools. Through a comprehensive literature review, we analyzed [...] Read more.

Immune checkpoint inhibitors (ICIs) have transformed melanoma treatment; however, predicting patient responses remains a significant challenge. This study reviews the potential of artificial intelligence (AI) to optimize ICI therapy in melanoma by integrating various diagnostic tools. Through a comprehensive literature review, we analyzed studies on AI applications in melanoma immunotherapy, focusing on predictive modeling, biomarker identification, and treatment response prediction. Key findings highlight the efficacy of AI in improving ICI outcomes. Machine learning models successfully identified prognostic cytokine signatures linked to nivolumab clearance. The combination of AI with RNAseq analysis had the potential for the development of personalized treatment with ICIs. A machine learning-based approach was able to assess the risk-benefit ratio for the prediction of immune-related adverse events (irAEs) using the electronic health record (EHR) data. Deep learning algorithms demonstrated high accuracy in tumor microenvironment analysis, including tumor region identification and lymphocyte detection. AI-assisted quantification of tumor-infiltrating lymphocytes (TILs) proved prognostically valuable in primary melanoma and predictive of anti-PD-1 therapy response in metastatic cases. Integrating multiple diagnostic modalities, such as CT imaging and laboratory data, modestly enhanced predictive performance for 1-year survival in advanced cancers treated with immunotherapy. These findings underscore the potential of AI-driven approaches to refine biomarker identification, treatment prediction, and patient stratification in melanoma immunotherapy. While promising, clinical validation and implementation challenges remain. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

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24 pages, 2211 KiB

Open AccessReview

Mechanisms of Resistance to Anti-PD-1 Immunotherapy in Melanoma and Strategies to Overcome It

by Magdalena K. Zielińska, Magdalena Ciążyńska, Dorota Sulejczak, Piotr Rutkowski and Anna M. Czarnecka

Biomolecules 2025, 15(2), 269; https://doi.org/10.3390/biom15020269 - 12 Feb 2025

Viewed by 2105

Abstract

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of [...] Read more.

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells’ invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

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29 pages, 2853 KiB

Open AccessReview

Notch Signaling and PD-1/PD-L1 Interaction in Hepatocellular Carcinoma: Potentialities of Combined Therapies

by Annapaola Montagner, Andrea Arleo, Fabrizia Suzzi, Antonino B. D’Assoro, Fabio Piscaglia, Laura Gramantieri and Catia Giovannini

Biomolecules 2024, 14(12), 1581; https://doi.org/10.3390/biom14121581 - 11 Dec 2024

Cited by 1 | Viewed by 1524

Abstract

Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway [...] Read more.

Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway observed in HCC can affect immune cell response, reducing the efficacy of cancer immunotherapy. Here, we provide an overview of how Notch signaling regulates immune responses and present the therapeutic rationale for combining Notch signaling inhibition with ICIs to improve HCC treatment. Moreover, we propose using exosomes as non-invasive tools to assess Notch signaling activation in hepatic cancer cells, enabling accurate stratification of patients who can benefit from combined strategies. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

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13 pages, 298 KiB

Open AccessEditor’s ChoiceReview

Small-Cell Lung Cancer: Is Liquid Biopsy a New Tool Able to Predict the Efficacy of Immunotherapy?

by Rossella Fasano, Simona Serratì, Tania Rafaschieri, Vito Longo, Roberta Di Fonte, Letizia Porcelli and Amalia Azzariti

Biomolecules 2024, 14(4), 396; https://doi.org/10.3390/biom14040396 - 25 Mar 2024

Cited by 4 | Viewed by 2807

Abstract

Small-cell lung cancer (SCLC) cases represent approximately 15% of all lung cancer cases, remaining a recalcitrant malignancy with poor survival and few treatment options. In the last few years, the addition of immunotherapy to chemotherapy improved clinical outcomes compared to chemotherapy alone, resulting [...] Read more.

Small-cell lung cancer (SCLC) cases represent approximately 15% of all lung cancer cases, remaining a recalcitrant malignancy with poor survival and few treatment options. In the last few years, the addition of immunotherapy to chemotherapy improved clinical outcomes compared to chemotherapy alone, resulting in the current standard of care for SCLC. However, the advantage of immunotherapy only applies to a few SCLC patients, and predictive biomarkers selection are lacking for SCLC. In particular, due to some features of SCLC, such as high heterogeneity, elevated cell plasticity, and low-quality tissue samples, SCLC biopsies cannot be used as biomarkers. Therefore, the characterization of the tumor and, subsequently, the selection of an appropriate therapeutic combination may benefit greatly from liquid biopsy. Soluble factors, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) are now useful tools in the characterization of SCLC. This review summarizes the most recent data on biomarkers detectable with liquid biopsy, emphasizing their role in supporting tumor detection and their potential role in SCLC treatment choice. Full article

(This article belongs to the Special Issue Cancer Immunotherapy and the PD-1/PD-L1 Checkpoint Pathway)

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