Adaptive Immune Resistance: How Cancer Protects from Immune Attack

Abstract

Adaptive immune resistance is a process in which the cancer changes its phenotype in response to a cytotoxic or proinflammatory immune response, thereby evading it. This adaptive process is triggered by the specific recognition of cancer cells by T cells, which leads to the production of immune-activating cytokines. Cancers then hijack mechanisms developed to limit inflammatory and immune responses and protect themselves from the T-cell attack. Inhibiting adaptive immune resistance is the mechanistic basis of responses to PD-1 or PD-L1-blocking antibodies, and may be of relevance for the development of other cancer immunotherapy strategies.

Significance: Several new immunotherapy strategies to treat cancer are based on inhibiting processes through which cancer adapts and evades from an immune response. Recognizing the specific adaptive resistance mechanisms in each case is likely to allow the personalized development of immunotherapies tailored to block how a particular cancer protects itself from the immune system.

Figure 1. Examples of adaptive immune resistance

a) Specific recognition of tumor antigen by T cells leads to the production of interferons but also the expression of immune-inhibitory receptors like the programmed cell death-1 (PD-1). Cells within the tumor, including cancer cells and macrophages, react to the presence of interferons by expressing the ligand to PD-1 (PD-L1), which functionally inactivates the tumor-infiltrating T cells. b) T cells producing interferons lead to the expression of immune-suppressive molecules beyond PD-L1, including indolaimine-2,3-deoxygenase (IDO), which is a rate-limiting enzyme in the tryptophan metabolism and essential for adequate T cell functionality. c) The production of tumor-necrosis factor alpha (TNF-alpha) by tumor-specific T cells can result in the de-differentiation of melanoma cells to stop expressing melanosomal antigens such as gp100, and instead express neural crest antigens such as the nerve growth factor receptor (NGFR or CD271).

Figure 2. Treatment selection based on detecting adaptive immune resistance

Tumor biopsies from patients with advanced cancers may contain T cell infiltrates that trigger an adaptive immune resistant response. Defining the specific mechanism of this reactive tumor protection would allow tailoring the treatment of the patient to block that particular escape mechanism. For example, if T cells in tumors are turned off by PD-1:PD-L1 interactions then single agent anti-PD-1 or anti-PD-L1 would be the most appropriate therapy with high likelihood of success and avoiding additional toxicities from combinations. But if there are no T cells in tumor biopsies, then combination immunotherapies could be designed to bring T cells into tumors, or the immune system would need to be turned on by vaccination or genetically engineered using an adoptive cell transfer (ACT) approach with T cell receptors (TCR) or chimeric antigen receptors (CAR).