Cancers

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20 pages, 7311 KiB

Open AccessArticle

Recognition Dynamics of Cancer Mutations on the ERp57-Tapasin Interface

by Monikaben Padariya, Umesh Kalathiya, Douglas R. Houston and Javier Antonio Alfaro

Cancers 2020, 12(3), 737; https://doi.org/10.3390/cancers12030737 - 20 Mar 2020

Cited by 8 | Viewed by 3857

Abstract

Down regulation of the major histocompatibility class (MHC) I pathway plays an important role in tumour development, and can be achieved by suppression of HLA expression or mutations in the MHC peptide-binding pocket. The peptide-loading complex (PLC) loads peptides on the MHC-I molecule [...] Read more.

Down regulation of the major histocompatibility class (MHC) I pathway plays an important role in tumour development, and can be achieved by suppression of HLA expression or mutations in the MHC peptide-binding pocket. The peptide-loading complex (PLC) loads peptides on the MHC-I molecule in a dynamic multi-step assembly process. The effects of cancer variants on ERp57 and tapasin components from the MHC-I pathway is less known, and they could have an impact on antigen presentation. Applying computational approaches, we analysed whether the ERp57-tapasin binding might be altered by missense mutations. The variants H408R(ERp57) and P96L, D100A, G183R(tapasin) at the protein–protein interface improved protein stability (ΔΔG) during the initial screen of 14 different variants. The H408R(ERp57) and P96L(tapasin) variants, located close to disulphide bonds, were further studied by molecular dynamics (MD). Identifying intramolecular a-a’ domain interactions, MD revealed open and closed conformations of ERp57 in the presence and absence of tapasin. In wild-type and mutant ERp57-tapasin complexes, residues Val97, Ser98, Tyr100, Trp405, Gly407(ERp57) and Asn94, Cys95, Arg97, Asp100(tapasin) formed common H-bond interactions. Moreover, comparing the H-bond networks for P96L and H408R with each other, suggests that P96L(tapasin) improved ERp57-tapasin binding more than the H408R(ERp57) mutant. During MD, the C-terminus domain (that binds MHC-I) in tapasin from the ERp57(H408R)-tapasin complex moved away from the PLC, whereas in the ERp57-tapasin(P96L) system was oppositely displaced. These findings can have implications for the function of PLC and, ultimately, for the presentation of MHC-I peptide complex on the tumour cell surface. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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Review

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14 pages, 880 KiB

Open AccessEditor’s ChoiceReview

The Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy

by Matthew J. Woodall, Silke Neumann, Katrin Campbell, Sharon T. Pattison and Sarah L. Young

Cancers 2020, 12(5), 1230; https://doi.org/10.3390/cancers12051230 - 14 May 2020

Cited by 79 | Viewed by 7054

Abstract

Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, [...] Read more.

Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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21 pages, 660 KiB

Open AccessReview

Opportunities for Conventional and In Situ Cancer Vaccine Strategies and Combination with Immunotherapy for Gastrointestinal Cancers, A Review

by Rachid Bouzid, Maikel Peppelenbosch and Sonja I. Buschow

Cancers 2020, 12(5), 1121; https://doi.org/10.3390/cancers12051121 - 30 Apr 2020

Cited by 34 | Viewed by 4849

Abstract

Survival of gastrointestinal cancer remains dismal, especially for metastasized disease. For various cancers, especially melanoma and lung cancer, immunotherapy has been proven to confer survival benefits, but results for gastrointestinal cancer have been disappointing. Hence, there is substantial interest in exploring the usefulness [...] Read more.

Survival of gastrointestinal cancer remains dismal, especially for metastasized disease. For various cancers, especially melanoma and lung cancer, immunotherapy has been proven to confer survival benefits, but results for gastrointestinal cancer have been disappointing. Hence, there is substantial interest in exploring the usefulness of adaptive immune system education with respect to anti-cancer responses though vaccination. Encouragingly, even fairly non-specific approaches to vaccination and immune system stimulation, involving for instance influenza vaccines, have shown promising results, eliciting hopes that selection of specific antigens for vaccination may prove useful for at least a subset of gastrointestinal cancers. It is widely recognized that immune recognition and initiation of responses are hampered by a lack of T cell help, or by suppressive cancer-associated factors. In this review we will discuss the hurdles that limit efficacy of conventional cancer therapeutic vaccination methods (e.g., peptide vaccines, dendritic cell vaccination). In addition, we will outline other forms of treatment (e.g., radiotherapy, chemotherapy, oncolytic viruses) that also cause the release of antigens through immunogenic tumor cell death and can thus be considered unconventional vaccination methods (i.e., in situ vaccination). Finally, we focus on the potential additive value that vaccination strategies may have for improving the effect immunotherapy. Overall, a picture will emerge that although the field has made substantial progress, successful immunotherapy through the combination with cancer antigen vaccination, including that for gastrointestinal cancers, is still in its infancy, prompting further intensification of the research effort in this respect. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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19 pages, 509 KiB

Open AccessReview

Hyperprogression Under Immune Checkpoint-Based Immunotherapy—Current Understanding, The Role of PD-1/PD-L1 Tumour-Intrinsic Signalling, Future Directions and a Potential Large Animal Model

by Mikolaj Kocikowski, Katarzyna Dziubek and Maciej Parys

Cancers 2020, 12(4), 804; https://doi.org/10.3390/cancers12040804 - 27 Mar 2020

Cited by 18 | Viewed by 6450

Abstract

Immune evasion is a major challenge for the development of successful cancer treatments. One of the known mechanisms is the expression of immune checkpoints (ICs)—proteins regulating the immune cells activation. The advent of immunotherapy using monoclonal antibodies (mAbs) to block the immune checkpoint [...] Read more.

Immune evasion is a major challenge for the development of successful cancer treatments. One of the known mechanisms is the expression of immune checkpoints (ICs)—proteins regulating the immune cells activation. The advent of immunotherapy using monoclonal antibodies (mAbs) to block the immune checkpoint receptor-ligand interaction brought about a landslide improvement in the treatment responses, leading to a prompt approval of such therapeutics. In recent years, it was discovered that a subset of patients receiving IC blockade treatment experienced a previously unknown pattern of treatment response called hyperprogression (HP), characterised by rapid deterioration on initialisation of the therapy. HP represents an urgent issue for clinicians and drug developers, while posing questions about the adequacy of the current clinical trial process. Here, we briefly summarise the state of knowledge and propose new directions for research into HP mechanisms, focusing on tumour-intrinsic signalling of IC proteins malignantly expressed by cancer. We also discuss the potential role of spontaneously occurring canine cancer in the assessment of immunotherapeutics, which can provide the missing link between murine and human studies. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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17 pages, 2324 KiB

Open AccessReview

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

by Kamila Pawlicka, Umesh Kalathiya and Javier Alfaro

Cancers 2020, 12(3), 765; https://doi.org/10.3390/cancers12030765 - 24 Mar 2020

Cited by 36 | Viewed by 8061

Abstract

Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier [...] Read more.

Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism caused by genetic mutations or dys-regulation of the NMD pathway can lead to pathologies, including neurological disorders, immune diseases and cancers. The role of NMD in cancer development is complex, acting as both a promoter and a barrier to tumour progression. Cancer cells can exploit NMD for the downregulation of key tumour suppressor genes, or tumours adjust NMD activity to adapt to an aggressive immune microenvironment. The latter case might provide an avenue for therapeutic intervention as NMD inhibition has been shown to lead to the production of neoantigens that stimulate an immune system attack on tumours. For this reason, understanding the biology and co-option pathways of NMD is important for the development of novel therapeutic agents. Inhibitors, whose design can make use of the many structures available for NMD study, will play a crucial role in characterizing and providing diverse therapeutic options for this pathway in cancer and other diseases. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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19 pages, 1446 KiB

Open AccessReview

Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence

by Raju K. Vaddepally, Prakash Kharel, Ramesh Pandey, Rohan Garje and Abhinav B. Chandra

Cancers 2020, 12(3), 738; https://doi.org/10.3390/cancers12030738 - 20 Mar 2020

Cited by 873 | Viewed by 28645

Abstract

Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade [...] Read more.

Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has led to the modern era of immunotherapy in cancer treatment. Agents that release these immune brakes have shown activity to recover dysfunctional T cells and regress various cancer. Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death-1 (PD-1) play their role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family; it mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. Ipilimumab is the first and only FDA-approved CTLA-4 inhibitor; PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). Programmed Death-Ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy. PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are in the current list of the approved agents in addition to ipilimumab. In this review paper, we discuss the role of each immune checkpoint inhibitor (ICI), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their daily practice. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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30 pages, 8868 KiB

Open AccessReview

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

by Elżbieta Chruściel, Zuzanna Urban-Wójciuk, Łukasz Arcimowicz, Małgorzata Kurkowiak, Jacek Kowalski, Mateusz Gliwiński, Tomasz Marjański, Witold Rzyman, Wojciech Biernat, Rafał Dziadziuszko, Carla Montesano, Roberta Bernardini and Natalia Marek-Trzonkowska

Cancers 2020, 12(3), 683; https://doi.org/10.3390/cancers12030683 - 13 Mar 2020

Cited by 34 | Viewed by 8059

Abstract

In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of [...] Read more.

In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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42 pages, 2260 KiB

Open AccessReview

Dendritic Cells in Anticancer Vaccination: Rationale for Ex Vivo Loading or In Vivo Targeting

by Alexey V. Baldin, Lyudmila V. Savvateeva, Alexandr V. Bazhin and Andrey A. Zamyatnin, Jr.

Cancers 2020, 12(3), 590; https://doi.org/10.3390/cancers12030590 - 5 Mar 2020

Cited by 55 | Viewed by 9270

Abstract

Dendritic cells (DCs) have shown great potential as a component or target in the landscape of cancer immunotherapy. Different in vivo and ex vivo strategies of DC vaccine generation with different outcomes have been proposed. Numerous clinical trials have demonstrated their efficacy and [...] Read more.

Dendritic cells (DCs) have shown great potential as a component or target in the landscape of cancer immunotherapy. Different in vivo and ex vivo strategies of DC vaccine generation with different outcomes have been proposed. Numerous clinical trials have demonstrated their efficacy and safety in cancer patients. However, there is no consensus regarding which DC-based vaccine generation method is preferable. A problem of result comparison between trials in which different DC-loading or -targeting approaches have been applied remains. The employment of different DC generation and maturation methods, antigens and administration routes from trial to trial also limits the objective comparison of DC vaccines. In the present review, we discuss different methods of DC vaccine generation. We conclude that standardized trial designs, treatment settings and outcome assessment criteria will help to determine which DC vaccine generation approach should be applied in certain cancer cases. This will result in a reduction in alternatives in the selection of preferable DC-based vaccine tactics in patient. Moreover, it has become clear that the application of a DC vaccine alone is not sufficient and combination immunotherapy with recent advances, such as immune checkpoint inhibitors, should be employed to achieve a better clinical response and outcome. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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14 pages, 807 KiB

Open AccessReview

Mass Spectrometry-Based Identification of MHC-Associated Peptides

by Sachin Kote, Artur Pirog, Georges Bedran, Javier Alfaro and Irena Dapic

Cancers 2020, 12(3), 535; https://doi.org/10.3390/cancers12030535 - 26 Feb 2020

Cited by 29 | Viewed by 8010

Abstract

Neoantigen-based immunotherapies promise to improve patient outcomes over the current standard of care. However, detecting these cancer-specific antigens is one of the significant challenges in the field of mass spectrometry. Even though the first sequencing of the immunopeptides was done decades ago, today [...] Read more.

Neoantigen-based immunotherapies promise to improve patient outcomes over the current standard of care. However, detecting these cancer-specific antigens is one of the significant challenges in the field of mass spectrometry. Even though the first sequencing of the immunopeptides was done decades ago, today there is still a diversity of the protocols used for neoantigen isolation from the cell surface. This heterogeneity makes it difficult to compare results between the laboratories and the studies. Isolation of the neoantigens from the cell surface is usually done by mild acid elution (MAE) or immunoprecipitation (IP) protocol. However, limited amounts of the neoantigens present on the cell surface impose a challenge and require instrumentation with enough sensitivity and accuracy for their detection. Detecting these neopeptides from small amounts of available patient tissue limits the scope of most of the studies to cell cultures. Here, we summarize protocols for the extraction and identification of the major histocompatibility complex (MHC) class I and II peptides. We aimed to evaluate existing methods in terms of the appropriateness of the isolation procedure, as well as instrumental parameters used for neoantigen detection. We also focus on the amount of the material used in the protocols as the critical factor to consider when analyzing neoantigens. Beyond experimental aspects, there are numerous readily available proteomics suits/tools applicable for neoantigen discovery; however, experimental validation is still necessary for neoantigen characterization. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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23 pages, 1255 KiB

Open AccessReview

Ribonucleic Acid Engineering of Dendritic Cells for Therapeutic Vaccination: Ready ‘N Able to Improve Clinical Outcome?

by Yannick Willemen, Maarten Versteven, Marc Peeters, Zwi N. Berneman and Evelien L. J. Smits

Cancers 2020, 12(2), 299; https://doi.org/10.3390/cancers12020299 - 27 Jan 2020

Cited by 2 | Viewed by 3381

Abstract

Targeting and exploiting the immune system has become a valid alternative to conventional options for treating cancer and infectious disease. Dendritic cells (DCs) take a central place given their role as key orchestrators of immunity. Therapeutic vaccination with autologous DCs aims to stimulate [...] Read more.

Targeting and exploiting the immune system has become a valid alternative to conventional options for treating cancer and infectious disease. Dendritic cells (DCs) take a central place given their role as key orchestrators of immunity. Therapeutic vaccination with autologous DCs aims to stimulate the patient’s own immune system to specifically target his/her disease and has proven to be an effective form of immunotherapy with very little toxicity. A great amount of research in this field has concentrated on engineering these DCs through ribonucleic acid (RNA) to improve vaccine efficacy and thereby the historically low response rates. We reviewed in depth the 52 clinical trials that have been published on RNA-engineered DC vaccination, spanning from 2001 to date and reporting on 696 different vaccinated patients. While ambiguity prevents reliable quantification of effects, these trials do provide evidence that RNA-modified DC vaccination can induce objective clinical responses and survival benefit in cancer patients through stimulation of anti-cancer immunity, without significant toxicity. Succinct background knowledge of RNA engineering strategies and concise conclusions from available clinical and recent preclinical evidence will help guide future research in the larger domain of DC immunotherapy. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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38 pages, 1835 KiB

Open AccessEditor’s ChoiceReview

Current Perspectives in Cancer Immunotherapy

by Theodoulakis Christofi, Stavroula Baritaki, Luca Falzone, Massimo Libra and Apostolos Zaravinos

Cancers 2019, 11(10), 1472; https://doi.org/10.3390/cancers11101472 - 30 Sep 2019

Cited by 158 | Viewed by 16889

Abstract

Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and [...] Read more.

Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and their applications in immuno-oncology has helped us tremendously towards this aim. We are now moving towards the realization of personalized medicine, thus, significantly increasing our expectations for a more successful management of the disease. Here, we discuss the current immunotherapeutic approaches against cancer, including immune checkpoint blockade with an emphasis on anti-PD-L1 and anti-CTLA-4 monoclonal antibodies. We also analyze a growing list of other co-inhibitory and co-stimulatory markers and emphasize the mechanism of action of the principal pathway for each of these, as well as on drugs that either have been FDA-approved or are under clinical investigation. We further discuss recent advances in other immunotherapies, including cytokine therapy, adoptive cell transfer therapy and therapeutic vaccines. We finally discuss the modulation of gut microbiota composition and response to immunotherapy, as well as how tumor-intrinsic factors and immunological processes influence the mutational and epigenetic landscape of progressing tumors and response to immunotherapy but also how immunotherapeutic intervention influences the landscape of cancer neoepitopes and tumor immunoediting. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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24 pages, 1461 KiB

Open AccessReview

Design of Outer Membrane Vesicles as Cancer Vaccines: A New Toolkit for Cancer Therapy

by Yingxuan Zhang, Zheyan Fang, Ruizhen Li, Xiaotian Huang and Qiong Liu

Cancers 2019, 11(9), 1314; https://doi.org/10.3390/cancers11091314 - 6 Sep 2019

Cited by 65 | Viewed by 7065

Abstract

Cancer vaccines have been extensively studied in recent years and have contributed to exceptional achievements in cancer treatment. They are some of the most newly developed vaccines, although only two are currently approved for use, Provenge and Talimogene laherparepvec (T-VEC). Despite the approval [...] Read more.

Cancer vaccines have been extensively studied in recent years and have contributed to exceptional achievements in cancer treatment. They are some of the most newly developed vaccines, although only two are currently approved for use, Provenge and Talimogene laherparepvec (T-VEC). Despite the approval of these two vaccines, most vaccines have been terminated at the clinical trial stage, which indicates that although they are effective in theory, concerns still exist, including low antigenicity of targeting antigens and tumor heterogeneity. In recent years, with new understanding of the biological function and vaccine potential of outer membrane vesicles (OMVs), their potential application in cancer vaccine design deserves our attention. Therefore, this review focuses on the mechanisms, advantages, and prospects of OMVs as antigen-carrier vaccines in cancer vaccine development. We believe that OMV-based vaccines present a safe and effective cancer therapeutic option with broad application prospects. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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Other

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23 pages, 1044 KiB

Open AccessPerspective

MHC Class I Regulation: The Origin Perspective

by Alicja Sznarkowska, Sara Mikac and Magdalena Pilch

Cancers 2020, 12(5), 1155; https://doi.org/10.3390/cancers12051155 - 4 May 2020

Cited by 13 | Viewed by 5607

Abstract

Viral-derived elements and non-coding RNAs that build up “junk DNA” allow for flexible and context-dependent gene expression. They are extremely dense in the MHC region, accounting for flexible expression of the MHC I, II, and III genes and adjusting the level of immune [...] Read more.

Viral-derived elements and non-coding RNAs that build up “junk DNA” allow for flexible and context-dependent gene expression. They are extremely dense in the MHC region, accounting for flexible expression of the MHC I, II, and III genes and adjusting the level of immune response to the environmental stimuli. This review brings forward the viral-mediated aspects of the origin and evolution of adaptive immunity and aims to link this perspective with the MHC class I regulation. The complex regulatory network behind MHC expression is largely controlled by virus-derived elements, both as binding sites for immune transcription factors and as sources of regulatory non-coding RNAs. These regulatory RNAs are imbalanced in cancer and associate with different tumor types, making them promising targets for diagnostic and therapeutic interventions. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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