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PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (25 April 2024) | Viewed by 17387

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Prof. Dr. Patrizia Ferroni

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1. Interinstitutional Multidisciplinary Biobank (BioBIM), IRCCS San Raffaele Roma, 00166 Rome, Italy
2. Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
Interests: biomarker discovery; decision support systems; predictive medicine; artificial intelligence
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Prof. Dr. Fiorella Guadagni

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1. BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Roma, 00166 Rome, Italy
2. Department of Human Sciences & Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
Interests: biomarker discovery; cancer biomarkers; decision support systems; predictive medicine; artificial intelligence
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Prof. Dr. Mario Roselli

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Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
Interests: cancer chemotherapy; venous thromboembolism; decision support systems; predictive medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is well known that, outside of rare instances, the anti-cancer immune response is actually ineffectual, mostly due to the local immunosuppressive effects of the tumor itself. Among the possible mechanisms, the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are currently recognized as key molecules for tumor immune escape. Under physiological circumstances, in fact, the PD-1 / PD-L1 pathway acts as an immune checkpoint for protecting normal tissues from immune self-attack by curbing the effector T-cell responses. However, tumor cells also take advantage of this checkpoint to down-regulate the T cell effector function by expressing PD-L1. In addition to T-cells and tumor cells, PD-1 and PD-L1 are also expressed in many other cell types, including macrophages, neutrophils and stromal cells, which pose significant implications for the role of the tumor microenvironment (TME) in the mechanisms of PD-1/PD-L1 inhibitor therapy.

Immunotherapy based on PD-1/PD-L1 blockade has been proposed in the past decades and monoclonal antibodies targeting PD-1 or PD-L1 (e.g., nivolumab, pembrolizumab and atezolizumab) have been developed and tested in clinical trials, which confirmed their benefits in prolonging cancer patients’ survival in various settings, such as lung, gastric and breast cancer. However, the response rates of monotherapy are significantly limited in the majority of cases and many unanswered questions remain on the efficacy and safety of immune checkpoint inhibitors. Tailored approaches based on the use of molecular imaging or predictive markers in immunotherapy trials also represents an unmet need to improve patient outcomes and additional translational research on tumor tissue or liquid biopsies could advance significantly our knowledge in the field.

This Special Issue will focus on recent advances in the efficacy/safety profile of PD-1/PD-L1 blockade in cancer treatment, from biomarker-driven therapy to novel radiopharmaceuticals (immuno-PET radiotracers) and drug combinations. Evidence on the role of optimized combination detection markers to further improve the accuracy of PD-L1 in predicting the efficacy of PD-1/PD-L1 blockades and the application of artificial intelligence techniques in the field of personalized immunotherapy will be also welcomed.

Prof. Dr. Patrizia Ferroni
Prof. Dr. Fiorella Guadagni
Prof. Dr. Mario Roselli
Guest Editors

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Published Papers (8 papers)

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17 pages, 4920 KiB

Open AccessEditor’s ChoiceArticle

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1

by Negar Khazan, Emily R. Quarato, Niloy A. Singh, Cameron W. A. Snyder, Taylor Moore, John P. Miller, Masato Yasui, Yuki Teramoto, Takuro Goto, Sabeeha Reshi, Jennifer Hong, Naixin Zhang, Diya Pandey, Priyanka Srivastava, Alexandra Morell, Hiroki Kawano, Yuko Kawano, Thomas Conley, Deepak M. Sahasrabudhe, Naohiro Yano, Hiroshi Miyamoto, Omar Aljitawi, Jane Liesveld, Michael W. Becker, Laura M. Calvi, Alexander S. Zhovmer, Erdem D. Tabdanov, Nikolay V. Dokholyan, David C. Linehan, Jeanne N. Hansen, Scott A. Gerber, Ashoke Sharon, Manoj K. Khera, Peter W. Jurutka, Natacha Rochel, Kyu Kwang Kim, Rachael B. Rowswell-Turner, Rakesh K. Singh and Richard G. Moore Show full author list Hide full author list

Cancers 2023, 15(13), 3432; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15133432 - 30 Jun 2023

Cited by 1 | Viewed by 3518

Abstract

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8⁺T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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12 pages, 2370 KiB

Open AccessArticle

The Role of Native T1 and T2 Mapping Times in Identifying PD-L1 Expression and the Histological Subtype of NSCLCs

by Chandra Bortolotto, Gaia Messana, Antonio Lo Tito, Giulia Maria Stella, Alessandra Pinto, Chiara Podrecca, Riccardo Bellazzi, Alessia Gerbasi, Francesco Agustoni, Fei Han, Marcel Dominik Nickel, Domenico Zacà, Andrea Riccardo Filippi, Olivia Maria Bottinelli and Lorenzo Preda

Cancers 2023, 15(12), 3252; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15123252 - 20 Jun 2023

Viewed by 1308

Abstract

We investigated the association of T1/T2 mapping values with programmed death-ligand 1 protein (PD-L1) expression in lung cancer and their potential in distinguishing between different histological subtypes of non-small cell lung cancers (NSCLCs). Thirty-five patients diagnosed with stage III NSCLC from April 2021 to December 2022 were included. Conventional MRI sequences were acquired with a 1.5 T system. Mean T1 and T2 mapping values were computed for six manually traced ROIs on different areas of the tumor. Data were analyzed through RStudio. Correlation between T1/T2 mapping values and PD-L1 expression was studied with a Wilcoxon–Mann–Whitney test. A Kruskal–Wallis test with a post-hoc Dunn test was used to study the correlation between T1/T2 mapping values and the histological subtypes: squamocellular carcinoma (SCC), adenocarcinoma (ADK), and poorly differentiated NSCLC (PD). There was no statistically significant correlation between T1/T2 mapping values and PD-L1 expression in NSCLC. We found statistically significant differences in T1 mapping values between ADK and SCC for the periphery ROI (p-value 0.004), the core ROI (p-value 0.01), and the whole tumor ROI (p-value 0.02). No differences were found concerning the PD NSCLCs. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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16 pages, 4543 KiB

Open AccessEditor’s ChoiceArticle

Immuno-PET Imaging of Tumour PD-L1 Expression in Glioblastoma

by Gitanjali Sharma, Marta C. Braga, Chiara Da Pieve, Wojciech Szopa, Tatjana Starzetz, Karl H. Plate, Wojciech Kaspera and Gabriela Kramer-Marek

Cancers 2023, 15(12), 3131; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15123131 - 09 Jun 2023

Cited by 2 | Viewed by 2975

Abstract

There is no established method to assess the PD-L1 expression in brain tumours. Therefore, we investigated the suitability of affibody molecule (Z_PD-L1) radiolabelled with F-18 (Al¹⁸F) and Ga-68 to measure the expression of PD-L1 in xenograft mouse models of GBM. Mice bearing subcutaneous and orthotopic tumours were imaged 1 h post-radioconjugate administration. Ex vivo biodistribution studies and immunohistochemistry (IHC) staining were performed. Tumoural PD-L1 expression and CD4+/CD8+ tumour-infiltrating lymphocytes were evaluated in human GBM specimens. Z_PD-L1 was radiolabelled with radiochemical yields of 32.2 ± 4.4% (F-18) and 73.3 ± 1.8% (Ga-68). The cell-associated radioactivity in vitro was consistent with PD-L1 expression levels assessed with flow cytometry. In vivo imaging demonstrated that ¹⁸F-AlF-NOTA-Z_PD-L1 can distinguish between PD-L1 high-expressing tumours (U87-MGvIII) and PD-L1-negative ones (H292_PD-L1Ko). The radioconjugate was quickly cleared from the blood and normal tissues, allowing for high-contrast images of brain tumours as early as 1 h post-injection. ⁶⁸Ga-NOTA-Z_PD-L1 showed heterogeneous and diffuse accumulation that corresponded to the extensively infiltrating GCGR-E55 tumours involving contiguous lobes of the brain. Lastly, 39% of analysed GBM patient samples showed PD-L1+ staining of tumour cells that was associated with elevated levels of CD4+ and CD8+ lymphocytes. Our results suggest that the investigated radioconjugates are very promising agents with the potential to facilitate the future design of treatment regimens for GBM patients. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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14 pages, 1897 KiB

Open AccessArticle

[⁸⁹Zr]-Atezolizumab-PET Imaging Reveals Longitudinal Alterations in PDL1 during Therapy in TNBC Preclinical Models

by Adriana V. F. Massicano, Patrick N. Song, Ameer Mansur, Sharon L. White, Anna G. Sorace and Suzanne E. Lapi

Cancers 2023, 15(10), 2708; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15102708 - 11 May 2023

Cited by 4 | Viewed by 1787

Abstract

Triple-negative breast cancers (TNBCs) currently have limited treatment options; however, PD-L1 is an indicator of susceptibility to immunotherapy. Currently, assessment of PD-L1 is limited to biopsy samples. These limitations may be overcome with molecular imaging. In this work, we describe chemistry development and optimization, in vitro, in vivo, and dosimetry of [⁸⁹Zr]-Atezolizumab for PD-L1 imaging. Atezolizumab was conjugated to DFO and radiolabeled with ⁸⁹Zr. Tumor uptake and heterogeneity in TNBC xenograft and patient-derived xenograft (PDX) mouse models were quantified following [⁸⁹Zr]-Atezolizumab-PET imaging. PD-L1 expression in TNBC PDX models undergoing therapy and immunohistochemistry (IHC) was used to validate imaging. SUV from PET imaging was quantified and used to identify heterogeneity. PET/CT imaging using [⁸⁹Zr]-Atezolizumab identified a significant increase in tumor:muscle SUV_mean 1 and 4 days after niraparib therapy and revealed an increased trend in PD-L1 expression following other cytotoxic therapies. A preliminary dosimetry study indicated the organs that will receive a higher dose are the spleen, adrenals, kidneys, and liver. [⁸⁹Zr]-Atezolizumab PET/CT imaging reveals potential for the noninvasive detection of PD-L1-positive TNBC tumors and allows for quantitative and longitudinal assessment. This has potential significance for understanding tumor heterogeneity and monitoring early expression changes in PD-L1 induced by therapy. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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15 pages, 1567 KiB

Open AccessArticle

Novel Computed-Tomography-Based Transformer Models for the Noninvasive Prediction of PD-1 in Pre-Operative Settings

by Yi Wei, Meiyi Yang, Lifeng Xu, Minghui Liu, Feng Zhang, Tianshu Xie, Xuan Cheng, Xiaomin Wang, Feng Che, Qian Li, Qing Xu, Zixing Huang and Ming Liu

Cancers 2023, 15(3), 658; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030658 - 20 Jan 2023

Cited by 4 | Viewed by 1791

Abstract

The expression status of programmed cell death protein 1 (PD-1) in patients with hepatocellular carcinoma (HCC) is associated with the checkpoint blockade treatment responses of PD-1/PD-L1. Thus, accurately and preoperatively identifying the status of PD-1 has great clinical implications for constructing personalized treatment strategies. To investigate the preoperative predictive value of the transformer-based model for identifying the status of PD-1 expression, 93 HCC patients with 75 training cohorts (2859 images) and 18 testing cohorts (670 images) were included. We propose a transformer-based network architecture, ResTransNet, that efficiently employs convolutional neural networks (CNNs) and self-attention mechanisms to automatically acquire a persuasive feature to obtain a prediction score using a nonlinear classifier. The area under the curve, receiver operating characteristic curve, and decision curves were applied to evaluate the prediction model’s performance. Then, Kaplan–Meier survival analyses were applied to evaluate the overall survival (OS) and recurrence-free survival (RFS) in PD-1-positive and PD-1-negative patients. The proposed transformer-based model obtained an accuracy of 88.2% with a sensitivity of 88.5%, a specificity of 88.9%, and an area under the curve of 91.1% in the testing cohort. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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11 pages, 2276 KiB

Open AccessArticle

Hepatic Radiotherapy in Addition to Anti-PD-1 for the Treatment of Metastatic Uveal Melanoma Patients

by Ernesto Rossi, Francesco Cellini, Monica Maria Pagliara, Maria Grazia Sammarco, Romina Rose Pedone, Valentina Lancellotta, Luca Tagliaferri, Michela Quirino, Maria Antonietta Gambacorta, Maria Antonietta Blasi, Giampaolo Tortora and Giovanni Schinzari

Cancers 2023, 15(2), 493; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020493 - 13 Jan 2023

Cited by 6 | Viewed by 1781

Abstract

Uveal melanoma is the most common ocular tumor with frequent metastatic spread to the liver. Immune checkpoint inhibitors have demonstrated poor results in this disease. The addition of hepatic radiotherapy to anti-PD-1 could enhance the sensitivity to immunotherapy. In this study, patients treated with pembrolizumab and who have undergone hepatic radiotherapy have been retrospectively evaluated. Twenty-two patients have been considered. Six patients (27.3%) achieved a partial response and 3 (13.6%) a stable disease. Disease control rate was 40.9%. Thirteen patients (59.1%) had progression as best response. The median PFS was 4.8 months and 6 months PFS rate 45.4%. The median OS was 21.2 months, while 1 year OS rate was 72.7%. Longer survival was observed in patients who achieved a partial response on irradiated metastases (HR 0.23, 95% CI 0.06–0.83) or progressed after 6 months (HR 0.12—95% CI 0.03–0.44). No radiotherapy-related or grade 3–4 adverse events were reported. This study demonstrates that the addition of hepatic radiotherapy to anti-PD-1 treatment can be a valid option for the treatment of metastatic uveal melanoma, particularly for HLA A 02:01 negative patients. Prospective studies should be conducted to confirm these data. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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11 pages, 1838 KiB

Open AccessArticle

Correlation between PD-L1 Expression of Non-Small Cell Lung Cancer and Data from IVIM-DWI Acquired during Magnetic Resonance of the Thorax: Preliminary Results

by Chandra Bortolotto, Giulia Maria Stella, Gaia Messana, Antonio Lo Tito, Chiara Podrecca, Giovanna Nicora, Riccardo Bellazzi, Alessia Gerbasi, Francesco Agustoni, Robert Grimm, Domenico Zacà, Andrea Riccardo Filippi, Olivia Maria Bottinelli and Lorenzo Preda

Cancers 2022, 14(22), 5634; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14225634 - 16 Nov 2022

Cited by 3 | Viewed by 1407

Abstract

This study aims to investigate the correlation between intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters in magnetic resonance imaging (MRI) and programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC). Twenty-one patients diagnosed with stage III NSCLC from April 2021 to April 2022 were included. The tumors were distinguished into two groups: no PD-L1 expression (<1%), and positive PD-L1 expression (≥1%). Conventional MRI and IVIM-DWI sequences were acquired with a 1.5-T system. Both fixed-size ROIs and freehand segmentations of the tumors were evaluated, and the data were analyzed through a software using four different algorithms. The diffusion (D), pseudodiffusion (D*), and perfusion fraction (pf) were obtained. The correlation between IVIM parameters and PD-L1 expression was studied with Pearson correlation coefficient. The Wilcoxon–Mann–Whitney test was used to study IVIM parameter distributions in the two groups. Twelve patients (57%) had PD-L1 ≥1%, and 9 (43%) <1%. There was a statistically significant correlation between D* values and PD-L1 expression in images analyzed with algorithm 0, for fixed-size ROIs (189.2 ± 65.709 µm²/s × 10⁴ in no PD-L1 expression vs. 122.0 ± 31.306 µm²/s × 10⁴ in positive PD-L1 expression, p = 0.008). The values obtained with algorithms 1, 2, and 3 were not significantly different between the groups. The IVIM-DWI MRI parameter D* can reflect PD-L1 expression in NSCLC. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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20 pages, 1814 KiB

Open AccessSystematic Review

Defining Tumor Microenvironment as a Possible Target for Effective GEP-NENs Immunotherapy—A Systematic Review

by Paulina Chmiel, Paulina Rychcik-Pazyrska and Rafał Stec

Cancers 2023, 15(21), 5232; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15215232 - 31 Oct 2023

Cited by 1 | Viewed by 1632

Abstract

Neuroendocrine neoplasms (NENs) are a heterogenous and recurrent group of malignancies originating from neuroendocrine secretory cells diffused on all parts of the human body. Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) account for most NENs. Considering the abundance of possible origins, locations, and tumor specifications, there is still no consensus about optimal treatment options for these neoplasms. In light of the escalating immunotherapeutic approaches, it is crucial to define indications for such therapy in GEP-NETs. Bearing in mind the significance of pathophysiological mechanisms and tumor microenvironment (TME) impact on carcinogenesis, defining TME structure and correlation with the immune system in GEP-NETs appears essential. This paper aimed to assess the characterization of the tumor immune microenvironment for a better understanding of the possible therapeutic options in GEP-NETS. The authors performed a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 3800 articles identified through database searching, 292 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis. This paper sums up the research on the immune cell infiltrates, immune checkpoint expression, cytokine profile, neoangiogenesis, and microbiome in the TME of GEP-NETs. Full article

(This article belongs to the Special Issue PD-1/PD-L1 Immune Checkpoint Therapy: From Predictive Biomarkers to Noninvasive Imaging)

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