Oncology Meets Immunology: The Cancer-Immunity Cycle
- Daniel S. Chen 1. 3 ,
- Ira Mellman 2. 3. .
- 1 Stanford Medical Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
- 2 Department of Biochemistry Biophysics, University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA
- 3 Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Available online 25 July 2013
The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer.
The development of cancer immunotherapy has reached an important inflection point in the history of cancer therapy (reviewed in Mellman et al. 2011 ). Durable monotherapy responses are consistently being reported for a broad range of human cancers with several different agents (Hamid et al. 2013a ; Herbst et al. 2013 ; Hodi et al. 2010 ; Topalian et al. 2012b ), providing a compelling argument that cancer immunotherapy is active in a range of indications beyond melanoma, a disease often thought to be atypically immunogenic ( Jacobs et al. 2012 ). In addition to encouraging activity, many of the cancer immunotherapy approaches report safety profiles that are milder and more manageable than traditional or targeted (i.e. oncogene-centric) cancer therapies.
Cancer is characterized by the accumulation of a variable number of genetic alterations and the loss of normal cellular regulatory processes ( Tian et al. 2011 ). These events have long been known to result in the expression of neoantigens, differentiation antigens, or cancer testis antigens, which can lead to presentation of peptides bound to major histocompatibility class I (MHCI) molecules on the surface of cancer cells, distinguishing them from their normal counterparts. Since the work of Boon and colleagues, we have known that these cancer-specific peptide-MHCI complexes can be recognized by CD8 + T cells produced spontaneously in cancer patients ( Boon et al. 1994 ). However, even when T cell responses occurred, they rarely provided protective immunity nor could they be mobilized to provide a basis for therapy.
As demonstrated by elegant analyses of cancer in mice, the continued deletion of cancer cells expressing T cell targets (immune editing) may enable cancers to evolve to avoid attack ( Dunn et al. 2002 ). Despite these findings, recent results from human cancer have demonstrated that overcoming negative regulators to T cell responses in lymphoid organs (checkpoints) and in the tumor bed (immunostat function) are likely to explain the failure of immune protection in many patients ( Mullard, 2013 ). Factors in the tumor microenvironment can act to modulate the existing activated antitumor T cell immune response, acting as an immune rheostat or immunostat. This class of molecules, including PD-L1:PD-1 (reviewed in Chen et al. 2012 ; Topalian et al. 2012a ), emphasizes that the immune response in cancer reflects a series of carefully regulated events that may be optimally addressed not singly but as a group. The challenge now is to use this new understanding to develop new drugs and implement clinical strategies.
The articles contained in this issue each address key aspects of how the immune response can control or be manipulated to enhance anticancer immunity (Galon et al. 2013 ; Kalos and June, 2013 ; Motz and Coukos, 2013 ; Palucka and Banchereau, 2013 ; van den Boorn and Hartmann, 2013 ; Zitvogel et al. 2013 ). Here, we will integrate this information and consider how it might best be used in clinical development.
The Cancer-Immunity Cycle
For an anticancer immune response to lead to effective killing of cancer cells, a series of stepwise events must be initiated and allowed to proceed and expand iteratively. We refer to these steps as the Cancer-Immunity Cycle ( Figure 1 ). In the first step, neoantigens created by oncogenesis are released and captured by dendritic cells (DCs) for processing (step 1). In order for this step to yield an anticancer T cell response, it must be accompanied by signals that specify immunity lest peripheral tolerance to the tumor antigens be induced. Such immunogenic signals might include proinflammatory cytokines and factors released by dying tumor cells or by the gut microbiota ( Figure 2. Table 1 ). Next, DCs present the captured antigens on MHCI and MHCII molecules to T cells (step 2), resulting in the priming and activation of effector T cell responses against the cancer-specific antigens (step 3) that are viewed as foreign or against which central tolerance has been incomplete. The nature of the immune response is determined at this stage, with a critical balance representing the ratio of T effector cells versus T regulatory cells being key to the final outcome. Finally, the activated effector T cells traffic to (step 4) and infiltrate the tumor bed (step 5), specifically recognize and bind to cancer cells through the interaction between its T cell receptor (TCR) and its cognate antigen bound to MHCI (step 6), and kill their target cancer cell (step 7). Killing of the cancer cell releases additional tumor-associated antigens (step 1 again) to increase the breadth and depth of the response in subsequent revolutions of the cycle. In cancer patients, the Cancer-Immunity Cycle does not perform optimally. Tumor antigens may not be detected, DCs and T cells may treat antigens as self rather than foreign thereby creating T regulatory cell responses rather than effector responses, T cells may not properly home to tumors, may be inhibited from infiltrating the tumor, or (most importantly) factors in the tumor microenvironment might suppress those effector cells that are produced (reviewed by Motz and Coukos, 2013 ).
The Cancer-Immunity Cycle
The generation of immunity to cancer is a cyclic process that can be self propagating, leading to an accumulation of immune-stimulatory factors that in principle should amplify and broaden T cell responses. The cycle is also characterized by inhibitory factors that lead to immune regulatory feedback mechanisms, which can halt the development or limit the immunity. This cycle can be divided into seven major steps, starting with the release of antigens from the cancer cell and ending with the killing of cancer cells. Each step is described above, with the primary cell types involved and the anatomic location of the activity listed. Abbreviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T lymphocytes.