The hallmarks of successful anticancer immunotherapy

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Science Translational Medicine  19 Sep 2018:
Vol. 10, Issue 459, eaat7807
DOI: 10.1126/scitranslmed.aat7807


  • Fig. 1 Malignant cells in the regulation of tumor-targeting immune responses driven by immunotherapy.

    Several aspects of the biology of malignant cells affect the likelihood of anticancer immunotherapy to elicit robust clinical responses. During initiation (left), the abundance of tumor neoantigens (TNAs), which to some extent depends on mutational load, their quality (notably their resemblance to viral antigens), and the ability of malignant cells to emit danger signals as they die have a major influence on the elicitation of anticancer immunity by dendritic cells (DCs) and other antigen-presenting cells. Moreover, cancer cells compete for nutrients with immune effector cells and express co-inhibitory ligands and other factors including CD73 and lactate that mediate local immunosuppression (regulation; middle). Finally, during execution (right), the ability of cancer cells to properly present tumor neoantigens, respond to interferon gamma (IFN-γ) and granzyme B (GZMB), undergo regulated cell death (RCD), or mount cytoprotective autophagic responses determines their sensitivity to immune effectors. IFNGR, interferon gamma receptor; TME, tumor microenvironment.

  • Fig. 2 Impact of the tumor infiltrate on clinical responses to immunotherapy.

    Three interrelated but conceptually distinct aspects of the immunological tumor infiltrate determine the likelihood of cancer patients to respond to immunotherapy: (i) the relative abundance of effector versus suppressor cells (left), (ii) the localization of immune cells with respect to their malignant counterparts (middle), and (iii) the activation status of immune effectors (right).

  • Fig. 3 Regulation of anticancer immunity by the tumor stroma and endothelium.

    The tumor endothelium expresses FAS ligand (FASL) downstream of vascular endothelial growth factor A (VEGFA) and prostaglandin E2 (PGE2) signaling (1), hence favoring the preferential extravasation of CD4+CD25+FOXP3+ Treg cells (2) as a consequence of cytotoxic T lymphocyte (CTL) elimination. Cadherin 5 (CDH5) also contributes to the limited permeability of the tumor endothelium to immune effector cells (3). CD4+ TH1 cells secreting IFN-γ appear to participate in a bidirectional cross-talk with the tumor endothelium, resulting in vascular normalization and immune cell reprogramming (4). Cancer-associated fibroblasts (CAFs) secrete high amounts of TGF-β (5), resulting in the establishment of a dense stromal reaction commonly known as desmoplastic stroma. Protein tyrosine kinase 2 (PTK2; best known as FAK) activation in malignant cells and CAFs have been involved in this process (6). However, although TGF-β is involved in immune exclusion, the actual impact of the desmoplastic stroma on anticancer immunity remains to be clarified. CAFs can also delete tumor-targeting T cells via a contact-dependent mechanism involving Fas ligand (FASL) and programmed cell death 1 ligand 2 (PDCD1LG2; another PD-1 ligand best known as PD-L2; 7) and secrete matrix metalloproteinases (MMPs) that generate soluble NK cell-activating receptor (sNCAR) ligands (8). Hypoxia, lactate accumulation, and (at least in some tumors) the local microbiota also contribute to immunosuppression via a variety of mechanisms (9).

  • Fig. 4 Systemic hallmarks of successful anticancer immunotherapy.

    The likelihood of cancer patients to obtain clinical benefits from immunotherapy depends on their global immunological competence, which can be influenced by cancer- and treatment-unrelated factors including variations in genes involved in the elicitation, regulation, and execution of tumor-targeting immunity; by viral infections or pharmacological agents resulting in systemic immunosuppression; and by the composition of the gut microbiota. In addition, developing tumors (and some forms of treatment) can change the systemic immunological microenvironment by favoring the generation of immature myeloid cells with immunosuppressive activity, by altering the gut microbiome (dysbiosis), and by releasing cytokines and other factors that quench anticancer immune responses. Many of these changes are instrumental for tumors to resist to treatment, hence constituting promising targets for the development of novel therapeutic interventions. These and other circulating factors including indicators of the functional competence of immune effector cells may be harnessed as biomarkers to assist clinical decision-making.


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