Immune system in cancer radiotherapy: Resistance mechanisms and therapy perspectives

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.

Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape. Throughout these phases, tumour immunogenicity is edited, and immunosuppressive mechanisms that enable disease progression are acquired. The mechanisms of resistance to immunotherapy seem to broadly overlap with those used by cancers as they undergo immunoediting to evade detection by the immune system. In this Review, we discuss how a deeper understanding of the mechanisms underlying the cancer immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance.