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Special Issue "Cancer Immunoediting and Beyond"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 September 2020).

Special Issue Editors

Prof. Dr. Fabio Grizzi
E-Mail Website
Guest Editor
Prof. Dr. Elena Monica Borroni
E-Mail Website
Guest Editor
1. Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
2. Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy
Interests: immunology; immundeficiencies; tumors; chemokine receptors; signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Human cancer is one of the most complex dynamic diseases. Despite rapid advances in the fields of molecular and cell biology, it is still widely debated as to how neoplastic cells progress through carcinogenesis and acquire their metastatic ability. Evidence has been accumulating since the middle of the last century, from animal models as well as from investigations in cancer patients, that the immune system can recognize and reject tumors. Tumor cells are constantly eliminated by the immune system, but some of them establish a long-term equilibrium phase leading to tumor “immunoediting” (i.e., the relationship between the tumor cells and the immune system, which mainly consists of three phases named elimination, equilibrium, and escape) and, eventually, “evasion”. It is known that during this dynamical process, tumor cells tend to acquire adjunctive mutations, leading to a greater number of new antigens with the potential to initiate an immune response. Although many tumors evoke an immune response, tumor clearance by the immune system does not occur due to a suppressive tumor microenvironment. Tumor immunology has, therefore, a growing need to comprehend the components of the immune system that are important for tumor immunosurveillance and tumor rejection to understand how, when, and why they fail in cases of clinical disease.

This Special Issue will contain a collection of manuscripts that describe investigations into the different stages of tumor “immunoediting”, covering a range of model systems and tumor types. The latest research articles and reviews that aim to clarify concepts, interpret experimental data, indicate specific experiments, and categorize a rich body of knowledge on the basis of the similarities and/or shared behaviors of very different tumors are welcome.

Prof. Fabio Grizzi
Prof. Elena Monica Borroni
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor immunoediting
  • tumor complexity
  • immunotherapy
  • immuno-oncology
  • cancer heterogeneity
  • chemokines
  • cytokines
  • immunosurveillance
  • microenvironment
  • stromal remodeling
  • innate immunity
  • adaptive immunity
  • modeling
  • bioinformatics

Published Papers (11 papers)

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Research

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Article
Immunogenomic Identification for Predicting the Prognosis of Cervical Cancer Patients
Int. J. Mol. Sci. 2021, 22(5), 2442; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052442 - 28 Feb 2021
Cited by 2 | Viewed by 942
Abstract
Cervical cancer is primarily caused by the infection of high-risk human papillomavirus (hrHPV). Moreover, tumor immune microenvironment plays a significant role in the tumorigenesis of cervical cancer. Therefore, it is necessary to comprehensively identify predictive biomarkers from immunogenomics associated with cervical cancer prognosis. [...] Read more.
Cervical cancer is primarily caused by the infection of high-risk human papillomavirus (hrHPV). Moreover, tumor immune microenvironment plays a significant role in the tumorigenesis of cervical cancer. Therefore, it is necessary to comprehensively identify predictive biomarkers from immunogenomics associated with cervical cancer prognosis. The Cancer Genome Atlas (TCGA) public database has stored abundant sequencing or microarray data, and clinical data, offering a feasible and reliable approach for this study. In the present study, gene profile and clinical data were downloaded from TCGA, and the Immunology Database and Analysis Portal (ImmPort) database. Wilcoxon-test was used to compare the difference in gene expression. Univariate analysis was adopted to identify immune-related genes (IRGs) and transcription factors (TFs) correlated with survival. A prognostic prediction model was established by multivariate cox analysis. The regulatory network was constructed and visualized by correlation analysis and Cytoscape, respectively. Gene functional enrichment analysis was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 204 differentially expressed IRGs were identified, and 22 of them were significantly associated with the survival of cervical cancer. These 22 IRGs were actively involved in the JAK-STAT pathway. A prognostic model based on 10 IRGs (APOD, TFRC, GRN, CSK, HDAC1, NFATC4, BMP6, IL17RD, IL3RA, and LEPR) performed moderately and steadily in squamous cell carcinoma (SCC) patients with FIGO stage I, regardless of the age and grade. Taken together, a risk score model consisting of 10 novel genes capable of predicting survival in SCC patients was identified. Moreover, the regulatory network of IRGs associated with survival (SIRGs) and their TFs provided potential molecular targets. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Article
Transcriptional Activity and Stability of CD39+CD103+CD8+ T Cells in Human High-Grade Endometrial Cancer
Int. J. Mol. Sci. 2020, 21(11), 3770; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113770 - 27 May 2020
Cited by 4 | Viewed by 1204
Abstract
Tumor-infiltrating CD8+ T cells (TIL) are of the utmost importance in anti-tumor immunity. CD103 defines tumor-resident memory T cells (TRM cells) associated with improved survival and response to immune checkpoint blockade (ICB) across human tumors. Co-expression of CD39 and CD103 marks tumor-specific [...] Read more.
Tumor-infiltrating CD8+ T cells (TIL) are of the utmost importance in anti-tumor immunity. CD103 defines tumor-resident memory T cells (TRM cells) associated with improved survival and response to immune checkpoint blockade (ICB) across human tumors. Co-expression of CD39 and CD103 marks tumor-specific TRM with enhanced cytolytic potential, suggesting that CD39+CD103+ TRM could be a suitable biomarker for immunotherapy. However, little is known about the transcriptional activity of TRM cells in situ. We analyzed CD39+CD103+ TRM cells sorted from human high-grade endometrial cancers (n = 3) using mRNA sequencing. Cells remained untreated or were incubated with PMA/ionomycin (activation), actinomycin D (a platinum-like chemotherapeutic that inhibits transcription), or a combination of the two. Resting CD39+CD103+ TRM cells were transcriptionally active and expressed a characteristic TRM signature. Activated CD39+CD103+ TRM cells differentially expressed PLEK, TWNK, and FOS, and cytokine genes IFNG, TNF, IL2, CSF2 (GM-CSF), and IL21. Findings were confirmed using qPCR and cytokine production was validated by flow cytometry of cytotoxic TIL. We studied transcript stability and found that PMA-responsive genes and mitochondrial genes were particularly stable. In conclusion, CD39+CD103+ TRM cells are transcriptionally active TRM cells with a polyfunctional, reactivation-responsive repertoire. Secondly, we hypothesize that differential regulation of transcript stability potentiates rapid responses upon TRM reactivation in tumors. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Article
Characterization of a Novel Murine Colon Carcinoma Subline with High-Metastatic Activity Established by In Vivo Selection Method
Int. J. Mol. Sci. 2020, 21(8), 2829; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082829 - 18 Apr 2020
Viewed by 1203
Abstract
The establishment of cancer cell lines, which have different metastatic abilities compared with the parental cell, is considered as an effective approach to investigate mechanisms of metastasis. A highly metastatic potential mouse colon cancer cell subline, Colon-26MGS, was derived from the parental cell [...] Read more.
The establishment of cancer cell lines, which have different metastatic abilities compared with the parental cell, is considered as an effective approach to investigate mechanisms of metastasis. A highly metastatic potential mouse colon cancer cell subline, Colon-26MGS, was derived from the parental cell line Colon-26 by in vivo selection using continuous subcutaneous implanting to immunocompetent mice. To clarify the mechanisms involved in the enhancement of metastasis, morphological characteristics, cell proliferation, and gene expression profiles were compared between Colon-26MGS and the parental cell. Colon-26MGS showed over 10 times higher metastatic ability compared with the parental cell, but there were no differences in morphological characteristics and in vitro proliferation rates. In addition, the Colon-26MGS-bearing mice exhibited no marked change of splenocyte population and lung pre-metastatic niche with tumor-free mice, but there were significant differences compared to Colon-26-bearing mice. RNA-seq analyses indicated that immune costimulatory molecules were significantly up-regulated in Colon-26MGS. These results suggest that Colon-26MGS showed not only higher metastatic activity, but also less induction property of host immune response compared to parental Colon-26. Colon-26MGS has proven to be a novel useful tool for studying multiple mechanisms involving metastasis enhancement. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Article
Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma—An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer
Int. J. Mol. Sci. 2020, 21(6), 2020; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062020 - 16 Mar 2020
Cited by 8 | Viewed by 1209
Abstract
We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations [...] Read more.
We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations of key markers of immune activation and tissue damage it would be possible to detect the onset of anticancer immune reaction as well as of immunologic adverse effects which might become crucial for optimization as well as safety of immune checkpoint inhibitor treatment. We analyzed time courses of routine laboratory values of serum tumor markers as well as of markers of immune activation in 17 patients with metastasized malignant melanoma receiving checkpoint inhibition and weekly laboratory controls. A parallel serum level increase of interleukin-6 and the tumor marker S100B could be identified in 13 patients, suggesting that the onset of tolerance breakage under checkpoint inhibition may be identified and measured. Immune-related adverse events in the patients were also accompanied by a peak of IL-6. In six patients, the onset of a putative anticancer immune reaction and the beginning of immunologic adverse events occurred in the same treatment cycle; in six patients the immunologic adverse reactions took place in separate cycles. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Article
DEK Is a Potential Biomarker Associated with Malignant Phenotype in Gastric Cancer Tissues and Plasma
Int. J. Mol. Sci. 2019, 20(22), 5689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225689 - 13 Nov 2019
Cited by 5 | Viewed by 1074
Abstract
Gastric cancer (GC) is the second most widespread cause of cancer-related mortality worldwide. The discovery of novel biomarkers of oncoproteins can facilitate the development of therapeutic strategies for GC treatment. In this study, we identified novel biomarkers by integrating isobaric tags for relative [...] Read more.
Gastric cancer (GC) is the second most widespread cause of cancer-related mortality worldwide. The discovery of novel biomarkers of oncoproteins can facilitate the development of therapeutic strategies for GC treatment. In this study, we identified novel biomarkers by integrating isobaric tags for relative and absolute quantitation (iTRAQ), a human plasma proteome database, and public Oncomine datasets to search for aberrantly expressed oncogene-associated proteins in GC tissues and plasma. One of the most significantly upregulated biomarkers, DEK, was selected and its expression validated. Our immunohistochemistry (IHC) (n = 92) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 72) analyses disclosed a marked increase in DEK expression in tumor tissue, compared with paired nontumor mucosa. Importantly, significantly higher preoperative plasma DEK levels were detected in GC patients than in healthy controls via enzyme-linked immunosorbent assay (ELISA). In clinicopathological analysis, higher expression of DEK in both tissue and plasma was significantly associated with advanced stage and poorer survival outcomes of GC patients. Data from receiver operating characteristic (ROC) curve analysis disclosed a better diagnostic accuracy of plasma DEK than carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA 19.9), and C-reactive protein (CRP), highlighting its potential as an effective plasma biomarker for GC. Plasma DEK is also more sensitive in tumor detection than the other three biomarkers. Knockdown of DEK resulted in inhibition of GC cell migration via a mechanism involving modulation of matrix metalloproteinase MMP-2/MMP-9 level and vice versa. Our results collectively support plasma DEK as a useful biomarker for making diagnosis and prognosis of GC patients. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Article
Identification of 15 T Cell Restricted Genes Evaluates T Cell Infiltration of Human Healthy Tissues and Cancers and Shows Prognostic and Predictive Potential
Int. J. Mol. Sci. 2019, 20(20), 5242; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205242 - 22 Oct 2019
Cited by 2 | Viewed by 1834
Abstract
T cell gene signatures are used to evaluate T cell infiltration of non-lymphoid tissues and cancers in both experimental and clinical settings. However, some genes included in the available T cell signatures are not T cell-restricted. Herein, we propose a new human T [...] Read more.
T cell gene signatures are used to evaluate T cell infiltration of non-lymphoid tissues and cancers in both experimental and clinical settings. However, some genes included in the available T cell signatures are not T cell-restricted. Herein, we propose a new human T cell signature that has been developed via a six-step procedure and comprises 15 T cell restricted genes. We demonstrate the new T cell signature, named signature-H, that differs from other gene signatures since it shows higher sensitivity and better predictivity in the evaluation of T cell infiltration in healthy tissues as well as 32 cancers. Further, results from signature-H are highly concordant with the immunohistochemistry methods currently used for assessing the prognosis of neuroblastoma, as demonstrated by the Kaplan–Meier curves of patients ranked by tumor T cell infiltration. Moreover, T cell infiltration levels calculated using signature-H correlate with the risk groups determined by the staging of the neuroblastoma. Finally, multiparametric analysis of tumor-infiltrating T cells based on signature-H let us favorably predict the response of melanoma to the anti-PD-1 antibody nivolumab. These findings suggest that signature-H evaluates T cell infiltration levels of tissues and may be used as a prognostic tool in the precision medicine perspective after appropriate clinical validation. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Review

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Review
Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma
Int. J. Mol. Sci. 2020, 21(17), 6083; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176083 - 24 Aug 2020
Cited by 4 | Viewed by 794
Abstract
Oral squamous cell carcinoma (OSCC) is the 10th most frequent human malignancy and is thus a global burden. Despite some progress in diagnosis and therapy, patients’ overall survival rate, between 40 and 55%, has stagnated over the last four decades. Since the tumor [...] Read more.
Oral squamous cell carcinoma (OSCC) is the 10th most frequent human malignancy and is thus a global burden. Despite some progress in diagnosis and therapy, patients’ overall survival rate, between 40 and 55%, has stagnated over the last four decades. Since the tumor node metastasis (TNM) system is not precise enough to predict the disease outcome, additive factors for diagnosis, prognosis, prediction and therapy resistance are urgently needed for OSCC. One promising candidate is the hypoxia inducible factor-1 (HIF-1), which functions as an early regulator of tumor aggressiveness and is a key promoter of energy adaptation. Other parameters comprise the composition of the tumor microenvironment, which determines the availability of nutrients and oxygen. In our opinion, these general processes are linked in the pathogenesis of OSCC. Based on this assumption, the review will summarize the major features of the HIF system-induced activities, its target proteins and related pathways of nutrient utilization and metabolism that are essential for the initiation, progression and therapeutic stratification of OSCC. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Review
Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia
Int. J. Mol. Sci. 2020, 21(16), 5696; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165696 - 08 Aug 2020
Cited by 2 | Viewed by 1301
Abstract
Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 [...] Read more.
Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Review
Exercise Oncology and Immuno-Oncology; A (Future) Dynamic Duo
Int. J. Mol. Sci. 2020, 21(11), 3816; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113816 - 27 May 2020
Cited by 4 | Viewed by 1675
Abstract
Recent advances in clinical oncology is based on exploiting the capacity of the immune system to combat cancer: immuno-oncology. Thus, immunotherapy of cancer is now used to treat a variety of malignant diseases. A striking feature is that even patients with late-stage disease [...] Read more.
Recent advances in clinical oncology is based on exploiting the capacity of the immune system to combat cancer: immuno-oncology. Thus, immunotherapy of cancer is now used to treat a variety of malignant diseases. A striking feature is that even patients with late-stage disease may experience curative responses. However, most patients still succumb to disease, and do not benefit from treatment. Exercise has gained attention in clinical oncology and has been used for many years to improve quality of life, as well as to counteract chemotherapy-related complications. However, more recently, exercise has garnered interest, largely due to data from animal studies suggesting a striking therapeutic effect in preclinical cancer models; an effect largely mediated by the immune system. In humans, physical activity is associated with a lower risk for a variety of malignancies, and some data suggest a positive clinical effect for cancer patients. Exercise leads to mobilization of cells of the immune system, resulting in redistribution to different body compartments, and in preclinical models, exercise has been shown to lead to immunological changes in the tumor microenvironment. This suggests that exercise and immunotherapy could have a synergistic effect if combined. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Review
Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges
Int. J. Mol. Sci. 2020, 21(2), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020597 - 17 Jan 2020
Cited by 21 | Viewed by 2867
Abstract
The immune system plays a dual role in tumor evolution—it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as [...] Read more.
The immune system plays a dual role in tumor evolution—it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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Review
Targeting Immune-Related Biological Processes in Solid Tumors: We do Need Biomarkers
Int. J. Mol. Sci. 2019, 20(21), 5452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215452 - 01 Nov 2019
Cited by 27 | Viewed by 2447
Abstract
Immunotherapy has become the standard-of-care in many solid tumors. Despite the significant recent achievements in the diagnosis and treatment of cancer, several issues related to patients’ selection for immunotherapy remain unsolved. Multiple lines of evidence suggest that, in this setting, the vision of [...] Read more.
Immunotherapy has become the standard-of-care in many solid tumors. Despite the significant recent achievements in the diagnosis and treatment of cancer, several issues related to patients’ selection for immunotherapy remain unsolved. Multiple lines of evidence suggest that, in this setting, the vision of a single biomarker is somewhat naïve and imprecise, given that immunotherapy does not follow the rules that we have experienced in the past for targeted therapies. On the other hand, additional immune-related biomarkers that are reliable in real-life clinical practice remain to be identified. Recently, the immune-checkpoint blockade has been approved in the US irrespective of the tumor site of origin. Further histology-agnostic approvals, coupled with with tumor-specific companion diagnostics and guidelines, are expected in this field. In addition, immune-related biomarkers can also have a significant prognostic value. In this review, we provide an overview of the role of these biomarkers and their characterization in the management of lung cancer, melanoma, colorectal cancer, gastric cancer, head and neck cancer, renal cell carcinoma, urothelial cancers, and breast cancer. Full article
(This article belongs to the Special Issue Cancer Immunoediting and Beyond)
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