Chromatin regulation and immune escape

Antigens expressed by cancer cells target them for elimination by tumor-infiltrating T cells (1). But, despite T cell recognition, advanced malignancies are often fatally progressive. T cell inhibitory (checkpoint) receptors, including programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4), contribute to immune suppression and dysfunction in tumors. Checkpoint inhibitors (CPIs) developed to block these pathways and derepress T cell activity have considerably improved outcomes for various cancer types. However, beyond certain rare and highly sensitive tumors (2), responses remain limited to a fraction of patients, and both primary and acquired resistance are frequently observed. Although much work has focused on defining and overcoming T cell–intrinsic inhibitory mechanisms, such as checkpoint expression, less is known about what regulates tumor cell sensitivity to T cell attack. On pages 801 and 770 of this issue, Miao et al. (3) and Pan et al. (4), respectively, find that chromatin remodeling pathways contribute to cancer cell immune resistance through control of interferon-stimulated gene (ISG) expression. This has implications for our understanding of why CPIs fail and suggests that targeting these pathways may enhance tumor immunotherapy

Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer

The past few years have witnessed something of a renaissance in the field of cancer immunotherapy, relating largely to the clinical advances that have been associated with the development of monoclonal antibodies targeting the immune inhibitory co-receptors CTLA-4 and PD-1 and to the pursuit of genetically modified antigen-redirected adoptive T-cell therapies. These advances are based on a more substantial understanding of the factors restricting effective immune therapies that has been derived from the study of pre-clinical models of tumour growth in immune competent mice. Just as the recognition of the importance of positive co-stimulatory signaling has been instrumental to recent advances in the development of genetically modified antigen-specific adoptive cellular therapies, an increasing awareness of the ability of tumours to subvert multiple immune inhibitory pathways, effectively blunting the development or expansion of any anti-tumour immunity, is fostering the development of novel therapies that appear active as monotherapies but may achieve their greatest impact in combinatorial regimens. This mini-review will focus on attempts to target co-inhibitory members of the immunoglobulin superfamily

Tumour heterogeneity and immune-modulation.

Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune-modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies

Allergens of the urushiol family promote mitochondrial dysfunction by inhibiting the electron transport at the level of cytochromes b and chemically modify cytochrome c1

BACKGROUND: Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by CD8+ effector T-cells and downregulated by CD4+ T-cells. However, the molecular mechanism by which urushiols stimulate innate immunity in the initial stages of this allergic reaction is poorly understood. Here we explore the sub-cellular mechanisms by which urushiols initiate the allergic response. RESULTS: Electron microscopy observations of mouse ears exposed to litreol (3-n-pentadecyl-10-enyl-catechol]) showed keratinocytes containing swollen mitochondria with round electron-dense inclusion bodies in the matrix. Biochemical analyses of sub-mitochondrial fractions revealed an inhibitory effect of urushiols on electron flow through the mitochondrial respiratory chain, which requires both the aliphatic and catecholic moieties of these allergens. Moreover, urushiols extracted from poison ivy/oak (mixtures of 3-n-pentadecyl-8,11,13 enyl/3-n-heptadecyl-8,11 enyl catechol) exerted a higher inhibitory effect on mitochondrial respiration than did pentadecyl catechol or litreol, indicating that the higher number of unsaturations in the aliphatic chain, stronger the allergenicity of urushiols. Furthermore, the analysis of radioactive proteins isolated from mitochondria incubated with 3H-litreol, indicated that this urushiol was bound to cytochrome c1. According to the proximity of cytochromes c1 and b, functional evidence indicated the site of electron flow inhibition was within complex III, in between cytochromes bL (cyt b566) and bH (cyt b562). CONCLUSION: Our data provide functional and molecular evidence indicating that the interruption of the mitochondrial electron transport chain constitutes an important mechanism by which urushiols initiates the allergic response. Thus, mitochondria may constitute a source of cellular targets for generating neoantigens involved in the T-cell mediated allergy induced by urushiols

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted

Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis

Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+ cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+ cells remain confined to a NK1.1lowNKp46low stage, but differentiate into NK1.1+NKp46+ cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling

APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

The APOBEC mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer

TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors

Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern. To overcome PD-L1–mediated immunosuppression and reduce CPI-associated toxicities, we used TALEN technology to render tumor-reactive T cells resistant to PD-1 signaling. Here, we demonstrate that inactivation of the PD-1 gene in melanoma-reactive CD8+ T cells and in fibrosarcoma-reactive polyclonal T cells enhanced the persistence of PD-1 gene-modified T cells at the tumor site and increased tumor control. These results illustrate the feasibility and potency of approaches incorporating advanced gene-editing technologies into ACT protocols to silence immune checkpoints as a strategy to overcome locally active immune escape pathways