The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598-608. ©2017 AACR.

https://mct.aacrjournals.org/content/molcanther/16/11/2598.full.pdf

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.

Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the "magic bullet" to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.

/pdf/anti-pd-1-and-anti-ctla-4-therapies-in-cancer-mechanisms-of-bppigkly0s.pdf

Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations.

Summary Background The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype. Methods We analysed whole-exome sequencing data from 5777 solid tumours, spanning 19 cancer types from The Cancer Genome Atlas. We compared the proportion and number of indels across the cohort, with a subset of results replicated in two independent datasets. We assessed in-silico tumour-specific neoantigen predictions by mutation type with pan-cancer analysis, together with RNAseq profiling in renal clear cell carcinoma cases (n=392), to compare immune gene expression across patient subgroups. Associations between indel burden and treatment response were assessed across four checkpoint inhibitor datasets. Findings We observed renal cell carcinomas to have the highest proportion (0·12) and number of indel mutations across the pan-cancer cohort (p −16 ), more than double the median proportion of indel mutations in all other cancer types examined. Analysis of tumour-specific neoantigens showed that enrichment of indel mutations for high-affinity binders was three times that of non-synonymous SNV mutations. Furthermore, neoantigens derived from indel mutations were nine times enriched for mutant specific binding, as compared with non-synonymous SNV derived neoantigens. Immune gene expression analysis in the renal clear cell carcinoma cohort showed that the presence of mutant-specific neoantigens was associated with upregulation of antigen presentation genes, which correlated ( r =0·78) with T-cell activation as measured by CD8-positive expression. Finally, analysis of checkpoint inhibitor response data revealed frameshift indel count to be significantly associated with checkpoint inhibitor response across three separate melanoma cohorts (p=4·7 × 10 −4 ). Interpretation Renal cell carcinomas have the highest pan-cancer proportion and number of indel mutations. Evidence suggests indels are a highly immunogenic mutational class, which can trigger an increased abundance of neoantigens and greater mutant-binding specificity. Funding Cancer Research UK, UK National Institute for Health Research (NIHR) at the Royal Marsden Hospital National Health Service Foundation Trust, Institute of Cancer Research and University College London Hospitals Biomedical Research Centres, the UK Medical Research Council, the Rosetrees Trust, Novo Nordisk Foundation, the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council.

Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis

COVID-19: Melatonin as a potential adjuvant treatment.

Zika Virus Causes Testis Damage and Leads to Male Infertility in Mice

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS-induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1β and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI.

Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome

Housekeeping genes (HKGs) are constitutively expressed with low variation across tissues/conditions. They are thought to be highly conserved and fundamental to cellular maintenance, with distinctive genomic features. Here we identify 1505 HKGs in the unicellular marine diatom Thalassiosira pseudonana based on an RNA-seq analysis of 232 samples taken under 12 experimental conditions over 0-72 h. We identify promising internal reference genes (IRGs) for T. pseudonana from the most stably expressed HKGs. A comparative analysis indicates < 18% of HKGs in T. pseudonana have orthologs in other eukaryotes, including other diatom species. Contrary to work on human tissues, T. pseudonana HKGs are longer than non-HKGs, due to elongated introns. More ancient HKGs tend to be shorter than more recent HKGs and expression levels of HKGs decrease more rapidly with gene length relative to non-HKGs. Our results indicate that HKGs are highly variable across the tree of life and thus unlikely to be universally fundamental for cellular maintenance. We hypothesize that the distinct genomic features of HKGs of T. pseudonana may be a consequence of selection pressures associated with high expression and low variance across conditions.

Yong Zhang

Papers

Zika Virus Causes Testis Damage and Leads to Male Infertility in Mice

Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome

Conservation and architecture of housekeeping genes in the model marine diatom Thalassiosira pseudonana.