No patient left behind: The promise of immune priming with epigenetic agents

Abstract

Checkpoint inhibitors, monoclonal antibodies that inhibit PD-1 or CTLA-4, have revolutionized the treatment of multiple cancers. Despite the enthusiasm for the clinical successes of checkpoint inhibitors, and immunotherapy, in general, only a minority of patients with specific tumor types actually benefit from treatment. Emerging evidence implicates epigenetic alterations as a mechanism of clinical resistance to immunotherapy. This review presents evidence for that association, summarizes the epi-based mechanisms by which tumors evade immunogenic cell death, discusses epigenetic modulation as a component of an integrated strategy to boost anticancer T cell effector function in relation to a tumor immunosuppression cycle and, finally, makes the case that the success of this no-patient-left-behind strategy critically depends on the toxicity profile of the epigenetic agent(s).

Keywords: Immunotherapy; checkpoint inhibitors; epigenetic modulation; immunogenic cell death; immunosuppression; resistance.

Figure 1.

(A) Hypermethylation and transcriptional silencing. A hallmark of cancer is hypermethylation of DNA sequences in the promoter region leading to transcriptional silencing. (B) Histone acetylation leads to a switch between transcriptionally repressive and permissive chromatin. Histone acetylation induces a change from compacted to a more ‘open’ chromatin state and increases the accessibility of transcription complexes to genomic DNA. Acetylation is an important factor for the regulation of gene expression.

Figure 2.

Epigenetic regulation of transcription. DNA is compressed in the nucleus as chromatin. The building block of chromatin is the nucleosome, which consists of 8 DNA wrapped histones.. Epigenetic regulation involves DNA methylation, histone acetylation and histone methylation that depending on the combination of modifications lead to transcriptional repression or transcriptional activation.

Figure 3.

The Immunoescape Cycle. To the left, the Antitumor Immunity Cycle illustrating the 7 main steps to stimulate an effective antitumor response. In cancer this cycle is interrupted at one or more steps to prevent specific T-cell immunity. Adapted from Oncology Meets Immunology: The Cancer-Immunity Cycle Daniel S. Chen and Ira Mellman Immunity 39, July 25, 2013. In a mirror image of the beneficial immunity cycle pictured to the left, which is responsible for the elimination of tumor cells, the harmful Immunoescape Cycle pictured to the right illustrates 7 different mechanisms by which the tumor corrupts or evades the 7 steps of the immunity cycle.

Figure 4.

PET-CT showing tumor central necrosis and pseudoprogression in a patient recruited in the Phase 1 clinical trial. The pathology report indicated that the rim was >90% necrotic suggesting an influx of lymphocytes.

Figure 5.

Naïve (T)cells require 2 signals to become activated: TCR/MHC and co-stimulation. The specific signal alone or the co-stimulatory signal alone leads to T cell anergy. The co-stimulatory signal is necessary for the synthesis and secretion of IL-2, which stimulates the T cell to divide and generate a larger population of memory and effector cells.

Figure 6.

Influence of hypoxia in the tumor on the innate and adaptive immune response. In general hypoxia suppresses the response of the immune system. The adaptive immune system includes cytotoxic T lymphocytes (CTL), T regulatory cells (T reg) and B cells. The innate immune system includes dendritic cells, myeloid derived suppressor cells (MDSC) and natural killer cells (NK).

Figure 7.

Innate vs adaptive resistance. PD-L1 can be constitutively expressed or induced adaptively if the right inflammatory cytokines are present in the immune environment.