Journal Articles

The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View

The collection of microbes that live in and on the human body - the human microbiome - can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell-cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach.

Author Info: (1) Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: xavierj@mskcc.org. (2) Department of Internal Medi

Author Info: (1) Program for Computational and Systems Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: xavierj@mskcc.org. (2) Department of Internal Medicine, Division of Infectious Diseases, The University of Michigan Medical School, Ann Arbor, MI, USA. (3) Department of Mathematics, Clarkson University, Potsdam, NY, USA. (4) GE Research, Niskayuna, NY, USA. (5) Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA. (6) Section of Hematology/Oncology, Department of Medicine, Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, IL, USA. (7) Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA. (8) Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA, USA. (9) Institute for Systems Biology, Seattle, WA, USA. (10) Hunter College, Department of Computer Science, New York, NY, USA. (11) Center for Applied Microbiome Science, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA. (12) Computational Biology Institute, Milken Institute School of Public Health, George Washington University, Washington, DC, USA. (13) Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. (14) Department of Microbiology and Medical Zoology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico. (15) Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA. (16) Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. (17) Seattle Children's Research Institute, Ben Towne Center for Childhood Cancer Research, Seattle, WA, USA. (18) Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. (19) University of Michigan, Ann Arbor, MI, USA. (20) Department of Surgery, Department of Obstetrics and Gynecology, and Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. (21) Department of Systems Biology, Columbia University, New York, NY, USA. (22) Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA. (23) School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (24) Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA. (25) Departments of Medicine, Anatomy, and Cell Biology, and of Infectious Diseases and Immunology, University of Florida, Gainesville, FL, USA. (26) Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. (27) University of Texas Southwestern Medical Center, Dallas, TX, USA. (28) Toyota Technological Institute at Chicago, Chicago, IL, USA. (29) Albert Einstein College of Medicine, Bronx, NY, USA. (30) The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact

Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed 'hyperprogressive disease' (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression.

Author Info: (1) University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (2) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Val

Author Info: (1) University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (2) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Vall Hebron Institute, Madrid, Spain. (4) Vall Hebron Institute, Madrid, Spain. (5) The University of Texas at Austin, Austin, TX, USA. (6) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: vsubbiah@mdanderson.org.

Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cell

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear. METHODS: Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer. RESULTS: Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour TH1 and CTL immune responses. CONCLUSIONS: Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.

Author Info: (1) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (2) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA.

Author Info: (1) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (2) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (3) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. Department of Microbiology, The Ohio State University, Columbus, OH, USA. (4) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (5) Department of Infection and Immunity, The Ohio State University, Columbus, OH, USA. (6) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (7) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (8) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (9) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (10) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (11) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (12) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (13) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (14) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. (15) Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA. abhay.satoskar@osumc.edu. Department of Microbiology, The Ohio State University, Columbus, OH, USA. abhay.satoskar@osumc.edu.

Prostaglandin E2 in a TLR3- and 7/8-agonist-based DC maturation cocktail generates mature, cytokine-producing, migratory DCs but impairs antigen cross-presentation to CD8(+) T cells

Mature dendritic cells (DCs) represent cellular adjuvants for optimal antigen presentation in cancer vaccines. Recently, a combination of prostaglandin E2 (PGE2) with Toll-like receptor agonists (TLR-P) was proposed as a new standard to generate superior cytokine-producing DCs with high migratory capacity. Here, we compare TLR-P DCs with conventional DCs matured only with the proinflammatory cytokines TNFalpha and IL-1ss (CDCs), focussing on the interaction of resulting DCs with CD8(+) T-cells. TLR-P matured DCs showed elevated expression of activation markers such as CD80 and CD83 compared to CDCs, together with a significantly higher migration capacity. Secretion of IL-6, IL-8, IL-10, and IL-12 was highest after 16 h in TLR-P DCs, and only TLR-P DCs secreted active IL-12p70. TLR-P DCs as well as CDCs successfully primed multifunctional CD8(+) T-cells from naive precursors specific for the peptide antigens Melan-A, NLGN4X, and PTP with comparable priming efficacy and T-cell receptor avidity. CD8(+) T-cells primed by TLR-P DCs showed significantly elevated expression of the integrin VLA-4 and a trend for higher T-cell numbers after expansion. In contrast, TLR-P DCs displayed a substantially reduced capability to cross-present CMVpp65 protein antigen to pp65-specific T cells, an effect that was dose-dependent on PGE2 during DC maturation and reproducible with several responder T-cell lines. In conclusion, TLR-P matured DCs might be optimal presenters of antigens not requiring processing such as short peptides. However, PGE2 seems less favorable for maturation of DCs intended to process and cross-present more complex vaccine antigens such as lysates, proteins or long peptides.

Author Info: (1) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (2) Laboratory for Stem Cell Processing and Cellular

Author Info: (1) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (2) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (3) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (4) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (5) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (6) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (7) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (8) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (9) CU Systems Medicine, University of Wurzburg, Wurzburg, Germany. Max Delbruck Center for Molecular Medicine (BIMSB/BIH), Berlin, Germany. (10) Department of Immunology, Interfaculty Institute for Cell Biology, University of Tubingen, Tubingen, Germany. (11) Department of Internal Medicine II, University Medical Center, Wurzburg, Germany. (12) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (13) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. (14) Laboratory for Stem Cell Processing and Cellular TherapyUniversity Medical Center, Children's Hospital, Wurzburg, Germany. eyrich_m@ukw.de. University Children's Hospital Wurzburg, Josef-Schneider-Strasse 3, Building D30, 97080, Wurzburg, Germany. eyrich_m@ukw.de.

Prediction and identification of novel HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from endocan

Background: Prediction and identification of cytotoxic T lymphocyte (CTL) epitopes from tumor associated antigens is a crucial step for the development of tumor immunotherapy strategy. Endocan has been identified as antigen overexpressed in various tumors. Methods: In this experiment, we predicted and identified HLA-A2-restricted CTL epitopes from endocan by using the following procedures. Firstly, we predicted the epitopes from the amino acid sequence of endocan by computer-based methods; Secondly, we determined the affinity of the predicted peptide with HLA-A2.1 molecule by peptide-binding assay; Thirdly, we elicited the primary T cell response against the predicted peptides in vitro; Lastly, we tested the specific CTLs toward endocan and HLA-A2.1 positive target cells. Results: These data demonstrated that peptides of endocan containing residues 4-12 and 9-17 could elicit specific CTLs producing interferon-gamma and cytotoxicity. Conclusions: Therefore, our findings suggested that the predicted peptides were novel HLA-A2.1-restricted CTL epitopes, and might provide promising target for tumor immunotherapy.

Author Info: (1) 1Department of orthopedics, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (2) 2Department of Neurology and Chongqin

Author Info: (1) 1Department of orthopedics, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (2) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (3) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (4) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (5) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (6) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555 (7) 2Department of Neurology and Chongqing key laboratory of cerebravascular disease, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160 China.grid.203458.80000 0000 8653 0555

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

BACKGROUND: Natural killer (NK) cells have potent antitumor activities. Nevertheless, adoptive transfer therapy of NK cells has gained very limited success in patients with solid tumors as most infused NK cells remain circulating in the peripheral blood instead of entering tumor sites. Chemokines and their receptors play important roles in NK cell distribution. Enhancing chemokine receptors on immune cells to match and be driven to tumor-specific chemokines may improve the therapeutic efficacy of NK cells. METHODS: The CCR5-CCL5 axis is critical in NK cell homing to tumor sites. Thus, we analyzed CCR5 expression on NK cells from patients with cancer and healthy donors. We then upregulated CCR5 and CCL5 with lentiviruses and oncolytic viruses in NK and tumor cells, respectively. Animal experiments were also carried out to test the efficacy of the combination of oncolytic virus with NK cells. RESULTS: In NK cells from patients with various solid tumors or healthy subjects, CCR5 was expressed at low levels before and after expansion in vitro. CCR5-engineered NK cells showed enhanced tumor infiltration and antitumor effects, but no complete regressions were noted in the in vivo tumor models. To further improve therapeutic efficacy, we constructed CCL5-expressing oncolytic vaccinia virus. In vitro data demonstrated that vaccinia virus can produce CCL5 in tumor cells while infectivity remained unaffected. Supernatants from tumor cells infected by CCL5-modified vaccinia virus enhanced the directional movement of CCR5-overexpressed NK cells but not green fluorescent protein (GFP)-expressing cells. More importantly, NK cells were resistant to the vaccinia virus and their functions were not affected after being in contact. In vivo assays demonstrated that CCL5-expressing vaccinia virus induced a greater accumulation of NK cells within tumor lesions compared with that of the prototype virus. CONCLUSION: Enhancement of matched chemokines and chemokine receptors is a promising method of increasing NK cell homing and therapeutic effects. Oncolytic vaccinia viruses that express specific chemokines can synergistically augment the efficacies of NK cell-based therapy.

Author Info: (1) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com.

Author Info: (1) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (2) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. (3) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (4) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (5) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. (6) Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com. (7) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China yizhang@zzu.edu.cn steve.thorne@westernoncolytics.com lifeng01@msn.com. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer

The prognostic value of Toll-like receptor 3 (TLR3) is debated in cancer, differing between tumor types, methods, and cell types. We recently showed for the first time that TLR3 expression on early stage non-small-cell lung cancer (NSCLC) results associated with a good prognosis. Here, we provide experimental evidences explaining the molecular reason behind TLR3's favorable prognostic role. We demonstrated that TLR3 activation in vitro induces apoptosis in lung cancer cell lines and, accordingly, that TLR3 expression is associated with caspase-3 activation in adenocarcinoma NSCLC specimens, both evaluated by immunohistochemistry. Moreover, we showed that TLR3 expression on cancer cells contributes to activate the CD103+ lung dendritic cell subset, that is specifically associated with processing of antigens derived from apoptotic cells and their presentation to CD8+ T lymphocytes. These findings point to the relevant role of TLR3 expression on lung cancer cells and support the use of TLR3 agonists in NSCLC patients to re-activate local innate immune response.

Author Info: (1) Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. (2) Pathological Anatomy Unit, ASST Grande Ospedale Metrop

Author Info: (1) Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. (2) Pathological Anatomy Unit, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy. (3) Immunotherapy of Human Tumors Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. (4) Pathological Anatomy Unit, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy. (5) First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. (6) First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. (7) Dipartimento di Scienze Biomediche per la Salute, Universita degli Studi di Milano, 20133 Milan, Italy. (8) Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. (9) Dipartimento di Scienze Biomediche per la Salute, Universita degli Studi di Milano, 20133 Milan, Italy.

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

The use of messenger RNA (mRNA) in gene therapy is increasing in recent years, due to its unique features compared to plasmid DNA: Transient expression, no need to enter into the nucleus and no risk of insertional mutagenesis. Nevertheless, the clinical application of mRNA as a therapeutic tool is limited by its instability and ability to activate immune responses; hence, mRNA chemical modifications together with the design of suitable vehicles result essential. This manuscript includes a revision of the strategies employed to enhance in vitro transcribed (IVT) mRNA functionality and efficacy, including the optimization of its stability and translational efficiency, as well as the regulation of its immunostimulatory properties. An overview of the nanosystems designed to protect the mRNA and to overcome the intra and extracellular barriers for successful delivery is also included. Finally, the present and future applications of mRNA nanomedicines for immunization against infectious diseases and cancer, protein replacement, gene editing, and regenerative medicine are highlighted.

Author Info: (1) Pharmacokinetics, Nanotechnology & Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigacion Lascaray ikergunea, University of the Basque Country UPV/EH

Author Info: (1) Pharmacokinetics, Nanotechnology & Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigacion Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01015 Vitoria-Gasteiz, Spain. (2) Pharmacokinetics, Nanotechnology & Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigacion Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01015 Vitoria-Gasteiz, Spain. (3) Pharmacokinetics, Nanotechnology & Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigacion Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01015 Vitoria-Gasteiz, Spain. (4) Pharmacokinetics, Nanotechnology & Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigacion Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01015 Vitoria-Gasteiz, Spain. (5) Pharmacokinetics, Nanotechnology & Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigacion Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01015 Vitoria-Gasteiz, Spain. (6) Pharmacokinetics, Nanotechnology & Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de investigacion Lascaray ikergunea, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01015 Vitoria-Gasteiz, Spain.

Immune-mediated adverse effects of immune-checkpoint inhibitors and their management in cancer

Within the past decade, immune-checkpoint inhibitors (ICPIs), including anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand 1 (PD-L1), and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, are undoubtfully the most remarkable advances in cancer therapy. The immune responses are modulated by these ICPIs via blocking the inhibitory PD-1/PD-L1 path and result in immune activation in the suppressive microenvironment of the tumor. While ICPIs result in benefits for numerous patients with malignancy and lead to disease control and survival, toxicity and safety problems have emerged as well. Although immune mediated adverse effects due to ICPIs could involve any organ system, skin, endocrine glands, and gastrointestinal tract, are one of the most commonly affected. Fortunately, in most of the cases, these immunemediated adverse effects (imAEs) are manageable, while in some cases these toxicities are fulminant and fatal and lead to the withdrawal of treatment. Numerous attempts have been started and are continuing to reduce the incidence rate of imAEs. Further studies are required for a better understanding of these imAEs, decrease the occurrence, and lighten the severity. In this work, we overview the imAEs and also, highlight the most important aspects of the imAEs management.

Author Info: (1) Department of Colorectal Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, Zhejiang Province, P.R. China. (2) K

Author Info: (1) Department of Colorectal Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, Zhejiang Province, P.R. China. (2) Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, P.R. China; Clinical Research Institute, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, P.R China. (3) Department of Colorectal Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, Zhejiang Province, P.R. China. (4) Department of Breast and Thyroid Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, Zhejiang Province, P.R. China. (5) Department of Gastrointestinal Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, Zhejiang Province, P.R. China. (6) Department of Colorectal Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, Zhejiang Province, P.R. China. (7) Student Research Committee, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. (8) Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, P.R. China; Clinical Research Institute, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, P.R China. Electronic address: mouxz@zju.edu.cn.

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens

Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4(+) and CD8(+) T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients' survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients.

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Univ

Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (3) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (4) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (5) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (6) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (7) Dipartimento di Medicina Molecolare, Sapienza Universita di Roma, 00161, Rome, Italy. (8) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (9) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (10) Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy. (11) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (12) Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy. IRCCS Neuromed, Pozzilli, Isernia, Italy. (13) Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Universita di Roma - Polo Pontino, 04100, Latina, Italy. (14) Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Universita di Roma - Polo Pontino, 04100, Latina, Italy. (15) UOC Oncologia Universitaria, ASL Latina (distretto Aprilia), Sapienza Universita di Roma, Via Giustiniano snc, 04011, Aprilia, Latina, Italy. (16) Dipartimento di Medicina Molecolare, Sapienza Universita di Roma, 00161, Rome, Italy. (17) Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. (18) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (19) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (20) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (21) Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (22) Unit of Pathology, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (23) Thoracic Surgery Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (24) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (25) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. vincenzo.barnaba@uniroma1.it. Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. vincenzo.barnaba@uniroma1.it. Istituto Pasteur - Fondazione Cenci Bolognetti, 00185, Rome, Italy. vincenzo.barnaba@uniroma1.it.

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