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      Advancing to the era of cancer immunotherapy

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          Abstract

          Cancer greatly affects the quality of life of humans worldwide and the number of patients suffering from it is continuously increasing. Over the last century, numerous treatments have been developed to improve the survival of cancer patients but substantial progress still needs to be made before cancer can be truly cured. In recent years, antitumor immunity has become the most debated topic in cancer research and the booming development of immunotherapy has led to a new epoch in cancer therapy. In this review, we describe the relationships between tumors and the immune system, and the rise of immunotherapy. Then, we summarize the characteristics of tumor‐associated immunity and immunotherapeutic strategies with various molecular mechanisms by showing the typical immune molecules whose antibodies are broadly used in the clinic and those that are still under investigation. We also discuss important elements from individual cells to the whole human body, including cellular mutations and modulation, metabolic reprogramming, the microbiome, and the immune contexture. In addition, we also present new observations and technical advancements of both diagnostic and therapeutic methods aimed at cancer immunotherapy. Lastly, we discuss the controversies and challenges that negatively impact patient outcomes.

          Abstract

          In this review, we present a clear view of the major factors and regulators associated with cancer immunotherapy and to provide our point of view on the latest available technologies and treatment methods for resolving clinical problems.

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          Most cited references333

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          Understanding the Warburg effect: the metabolic requirements of cell proliferation.

          In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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            PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

            Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.
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              The Immune Landscape of Cancer

              We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.
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                Author and article information

                Contributors
                xurh@sysucc.org.cn
                Journal
                Cancer Commun (Lond)
                Cancer Commun (Lond)
                10.1002/(ISSN)2523-3548
                CAC2
                Cancer Communications
                John Wiley and Sons Inc. (Hoboken )
                2523-3548
                24 June 2021
                September 2021
                : 41
                : 9 ( doiID: 10.1002/cac2.v41.9 )
                : 803-829
                Affiliations
                [ 1 ] Department of Medical Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. China
                [ 2 ] Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer Chinese Academy of Medical Sciences Guangzhou Guangdong 510060 P. R. China
                [ 3 ] Department of Clinical Research Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. China
                Author notes
                [*] [* ] Correspondence

                Prof. Rui‐Hua Xu, Sun Yat‐sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, Guangdong, P. R. China.

                Email: xurh@ 123456sysucc.org.cn

                [#]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-9771-8534
                Article
                CAC212178
                10.1002/cac2.12178
                8441060
                34165252
                02b76343-8788-49ad-94a9-b08e4f250ca7
                © 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 04 May 2021
                : 20 February 2021
                : 25 May 2021
                Page count
                Figures: 5, Tables: 0, Pages: 27, Words: 20055
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81930065
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                September 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:15.09.2021

                adverse effects,cancer,hyperprogressive disease,immune checkpoints,immunity,immunotherapy,metabolic reprogramming,microbiome,mutation

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