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Chapter 1

            Cancer and immunotherapy

            Cancer is a leading cause of death worldwide, accounting for 10 million deaths in 2020 with
            an expected annual increase. In general, cancer can be divided into two groups: metastatic
            (90% cause of cancer deaths) and non-metastatic [1]. Both primary and metastatic tumors are
            complex ecosystems composed of neoplastic cells, extracellular matrix (ECM), and non-ne-
            oplastic cells, which include resident mesenchymal support cells, endothelial cells, and infil-
            trated immune cells. Studies have demonstrated that inflammatory immune cells are essential
            players of cancer-related inflammation. For example, high levels of tumor-infiltrated T cells
            correlate with good prognosis in many solid cancers, on the other hand, high levels of mac-
            rophage infiltration correlate with a worse prognosis [2].

            Standard cancer therapy with traditional treatments (surgery, radiation therapy and chemo-
            therapy) often remains insufficient. With the improvement of the understanding of the role of
            the immune system in tumorigenesis and the anticancer immune response, immunotherapy
            currently is in rapid development and plays a significant role in current tumor therapy [3].
            Immunotherapeutic strategies include: 1) cancer vaccines, 2) oncolytic viruses, 3) adoptive
            transfer of ex vivo activated cytotoxic  cells, and 4) immune checkpoint blockade therapy
            with administration of blocking antibodies or recombinant proteins. Recent success of several
            immunotherapeutic interventions include sipuleucel-T, a cell-based therapy for the treatment
            of prostate cancer in 2010, and the approval of the anti-cytotoxic T lymphocyte-associated
            protein 4 (CTLA-4) antibody, ipilimumab, and of anti-programmed cell death protein 1 (PD-
            1) antibodies for the treatment of melanoma in 2011 and 2014, respectively. These successes
            have revitalized the field and highlight the opportunities that immunotherapeutic approaches
            can offer to assist the more traditional treatments [4].

            Immune checkpoint blockade therapy

            The tumor microenvironment (TME) is infiltrated with many types of innate and adaptive
            immune cells, whose immune surveillance functions are often suppressed or switched off by
            multiple tumor-driven mechanisms in a context-dependent manner [5]. One example of im-
            mune suppression is reflected by the ways that tumor cells downregulate the activity of stimu-
            latory immunoreceptors, while upregulating the activity of inhibitory immunoreceptors, e.g.,
            tumor cells can tune down T cell receptor (TCR)-mediated stimulatory signaling by down-
            regulating surface Major histocompatibility complex- I (MHC-I) level. On the other hand,
            tumor cells can tune up PD-1-mediated inhibitory signaling by upregulating the tumor-asso-
            ciated surface PD-L1 level [6]. Blocking the activation of inhibitory immunoreceptors with
            administration of antibodies or recombinant proteins can reinvigorate antitumor function of
            immune cells as demonstrated experimentally and translated to treatment of many types of
            cancer in the clinic. A few inhibitory immunoreceptors also known as immune checkpoints
            have been identified on immune cells and studied in cancer during the past decades, includ-
            ing Killer Ig-Like Receptor (KIR), T cell immunoglobulin and mucin-containing molecule 3
            (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), CD96, Lymphocyte-activation
            gene 3 (LAG-3), and PD-1 [7]. Immune checkpoint blockade therapy proofs successful to
            inhibit immune-checkpoint ligand-receptor axes by blocking antibodies, e.g., anti-PD-1/PD-
            L1 and anti-CTLA4 therapy have been approved by U.S. FDA to treat blood, skin, lung, liver,
            bladder, and kidney cancers [8, 9].


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