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Review
. 2011 Dec 21;480(7378):480-9.
doi: 10.1038/nature10673.

Cancer immunotherapy comes of age

Ira Mellman  1 , George Coukos, Glenn Dranoff
Affiliations
Review

Cancer immunotherapy comes of age

Ira Mellman et al. Nature. .

Abstract

Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After decades of disappointment, the tide has finally changed due to the success of recent proof-of-concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path to obtain a durable and long-lasting response in cancer patients.

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Figures

Figure 1
Figure 1. Generation and regulation of anti-tumor immunity
Understanding the events in generating and regulating anti-tumor immunity suggests at least three sites for therapeutic intervention: promoting the antigen presentation functions of DCs, promoting the production of protective T cell responses, and overcoming immunosuppression in the tumor bed. Anti-tumor immune responses must begin with the capture of tumor-associated antigens by DCs, either delivered exogenously or captured from dead or dying tumor cells. The DCs process the captured antigen for presentation or cross-presentation on MHC class II and class I molecules (respectively) and migrate to draining lymph nodes. If capture and presentation occurred in the presence of an immunogenic maturation stimulus, DCs will elicit anti-cancer effector T cell responses in the lymph node; if no such stimulus was received, DCs will instead induce tolerance leading to T cell deletion, anergy, or the production of Tregs. In the lymph node, antigen presentation to T cells will elicit responses depending on the type of DC maturation stimulus received and on the interaction of T-cell costimulatory molecules with their surface receptors on DCs. Thus, interaction of CD28 or OX40 with CD80/86 or OX40L will promote potentially protective T cell responses, while interaction of CTLA4 with CD80/86 or PD-1 with PD-L1/PD-L2 will suppress T cell responses, and possibly promote Treg formation. Antigen-educated T cells (along with B cells and NK cells) will exit the lymph node and enter the tumor bed, where a host of immunosuppressive defense mechanisms can be produced by tumors (or infiltrating myeloid cells) that oppose effector T cell function. These include the upregulation of PD-L1/L2 on the cancer cell surface, release of PGE2, arginase and IDO (all T cell suppressors), and the release of VEGF (triggered in part by intratumoral hypoxia), which inhibits T cell diapedesis from the vasculature and thus infiltration into the tumor bed.
Figure 2
Figure 2. Biologic activities of CTLA-4 antibody blockade
Upon encountering a dendritic cell presenting a cognate tumor antigen-derived peptide epitope and expressing B7 costimulatory molecules (CD80, CD86), specific anti-tumor T cells become activated through TCR and CD28 signaling. CTLA-4 is subsequently upregulated and preferentially engages B7 to attenuate T cell responses. Ipilimumab blocks CTLA-4 function, thereby allowing for enhanced T cell stimulation and more potent anti-tumor reactions. Ipilimumab may also antagonize CTLA-4 on regulatory T cells to limit their ability to suppress anti-tumor T cell effector responses (not shown). CTLA-4 antibody blockade compromises tolerance to some normal tissue antigens, provoking inflammatory toxicities that can especially impact the skin, pituitary gland, and intestine in human patients.
Figure 3
Figure 3. T cell targets for immunoregulatory antibody therapy
In addition to specific antigen recognition through the TCR, T cell activation is regulated through a balance of positive and negative signals provided by costimulatory receptors. These surface proteins are typically members of either the TNF receptor or B7 superfamilies. Agonistic antibodies directed against activating costimulatory molecules and blocking antibodies against negative costimulatory molecules may enhance T cell stimulation to promote tumor destruction.
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