A number of consensuses regarding cancer immunology have recently emerged from both preclinical immunotherapy models and analysis of cancer patients. First and foremost, the natural state of ...endogenous tumor reactive T cells is characterized by general hyporesponsiveness or anergy. This is likely due to a number of mechanisms that tumors use to induce tolerance as they develop. While many of the newer generation vaccines can effectively transfer antigen to and activate dendritic cells, T-cell tolerance remains a major barrier that is difficult to overcome by vaccination alone. Preclinical models demonstrate that for poorly immunogenic tumors, once tolerance has been established, therapeutic vaccines alone are ineffective at curing animals with a significant established tumor burden. However, combination strategies of vaccination together with inhibitors of immunologic checkpoints and agonists for co-stimulatory pathways are proving capable of overcoming tolerance and generating significant anti-tumor responses even in cases of established metastatic cancer.
Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into ...the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Neoadjuvant checkpoint blockade for cancer immunotherapy Topalian, Suzanne L; Taube, Janis M; Pardoll, Drew M
Science (American Association for the Advancement of Science),
01/2020, Letnik:
367, Številka:
6477
Journal Article
Recenzirano
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Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or ...PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti-PD-1 or anti-PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti-PD-1 and anti-PD-L1 efficacy.
The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and ...limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions. The complex biology of immune checkpoint pathways still contains many mysteries, and the full activity spectrum of checkpoint-blocking drugs, used alone or in combination, is currently the subject of intense study.
Summary
Regulatory T cells (Tregs) prevent autoimmunity and tissue damage resulting from excessive or unnecessary immune activation through their suppressive function. While their importance for ...proper immune control is undeniable, the stability of the Treg lineage has recently become a controversial topic. Many reports have shown dramatic loss of the signature Treg transcription factor Forkhead box protein 3 (Foxp3) and Treg function under various inflammatory conditions. Other recent studies demonstrate that most Tregs are extremely resilient in their expression of Foxp3 and the retention of suppressive function. While this debate is unlikely to be settled in the immediate future, improved understanding of the considerable heterogeneity within the Foxp3+ Treg population and how Treg subsets respond to ranging environmental cues may be keys to reconciliation. In this review, we discuss the diverse mechanisms responsible for the observed stability or instability of Foxp3+ Treg identity and function. These include transcriptional and epigenetic programs, transcript targeting, and posttranslational modifications that appear responsive to numerous elements of the microenvironment. These mechanisms for Treg functional modulation add to the discussion of Treg stability.
Immunology offers an unprecedented opportunity for the science-driven development of therapeutics. The successes of antibodies to the immunomodulatory receptor CTLA-4 and blockade of the ...immunoinhibitory receptor PD-1 in cancer immunotherapy, from gene discovery to patient benefit, have created a paradigm for driving such endeavors.
Deep learning algorithms have been utilized to achieve enhanced performance in pattern-recognition tasks. The ability to learn complex patterns in data has tremendous implications in immunogenomics. ...T-cell receptor (TCR) sequencing assesses the diversity of the adaptive immune system and allows for modeling its sequence determinants of antigenicity. We present DeepTCR, a suite of unsupervised and supervised deep learning methods able to model highly complex TCR sequencing data by learning a joint representation of a TCR by its CDR3 sequences and V/D/J gene usage. We demonstrate the utility of deep learning to provide an improved 'featurization' of the TCR across multiple human and murine datasets, including improved classification of antigen-specific TCRs and extraction of antigen-specific TCRs from noisy single-cell RNA-Seq and T-cell culture-based assays. Our results highlight the flexibility and capacity for deep neural networks to extract meaningful information from complex immunogenomic data for both descriptive and predictive purposes.
Highlights ► PD-1/B7-H1 are pivotal in maintaining an immunosuppressive tumor microenvironment. ► PD-1 and CTLA-4 play distinct roles in regulating immunity. ► B7-H1 upregulation on tumor cells ...likely reflects ‘adaptive resistance’. ► PD-1 blockade is active against NSCLC, thought to be a ‘non-immunogenic’ tumor. ► Monotherapies blocking PD-1 may be more effective in combinatorial regimens.
We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of ...double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.
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•DNMTis induce an interferon response in cancer cells by activating dsRNA sensors•DNMTis induce ERV demethylation and expression helping trigger the dsRNA response•DNMTi viral defense genes in melanoma track with patient response to immune therapy•DNMTi treatment sensitizes to anti-CTLA-4 immunotherapy in a melanoma mouse model
DNA methyltransferase inhibitors upregulate endogenous retroviruses in tumor cells to induce an growth-inhibiting immune response. High expression of the genes associated with the anti-viral response seems to potentiate a response to immune checkpoint therapy.
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung ...cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.
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