Cancer Immunity

Chen and Mellman (2013) elegantly summarized the interactions between cancer and the immune system as a multi-step, multi-tissue, highly-regulated process, which they named the “Cancer Immunity Cycle” due to the intrinsic self-propagating nature of the process (Figure 1).

In the first step, neoantigens created by oncogenesis are released and captured by antigen-presenting cells (APCs; eg. 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 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. Next, APCs 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). 

Many factors, both cellular and humoral as well as both stimulatory and inhibitory in nature, are involved in each of the cycle steps. 

Anti-cancer immunity resistance mechanisms:

Extrinsic mechanisms: This include IC, T cell exhaustion and phenotype change, immune suppressive cell populations (Tregs, MDSC, type II macrophages), and cytokine and metabolite release in the tumor microenvironment (CSF-1, tryptophan metabolites, TGF-b, adenosine).

Intrinsic mechanisms: Cancers have recently been recognized to activate signaling pathways that facilitate their evasion of immune-mediated destruction (eg. MAPK, PI3K, IFN, WTN/β-catenin, PTEN, epigenetic modifications within the tumor). Other intrinsic factors that lead to primary or adaptive resistance include lack of antigenic mutations, loss of tumor antigen expression, loss of HLA expression, alterations in antigen processing machinery, and constitutive PD-L1 expression.

On the other hand, mutations in DNA repair pathways can also arise spontaneously in tumors, leading to significantly increased mutational burden, and mounting evidence suggests that tumors with higher numbers of mutations are more sensitive to immunotherapies due to increased neoantigen display.

As part of the Cancer Research Institute's Breakthroughs in Cancer Immunotherapy Webinar Series (2015) Jeffrey S. Weber, M.D., Ph.D. discussed the cancer immunity cycle and the importance of antigen release and presentation to maximize the potential of immunotherapies. 

The articles in the specially commissioned Focus on Tumour  Immunology & immunotherapy (2012) from Nature Reviews Cancer and Nature Reviews Immunology, together with some recent Research Highlights, comprehensively describe respective components/aspects of the immune system complexity in cancer biology and the promise of immunotherapy.

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