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Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors.
Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, Zheng S, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N
Abstract -

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C(+) subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.

Illumina Summary -

Dendritic cells (DCs) and monocytes are immune cells composed of multiple specialized sub-types. Given their essential role in pathogen sensing and antigen presentation, fully characterizing their identities and interrelationships is critically important. Historically, they have been defined by morphological features, biological features, and restricted sets of surface markers. This approach has led to a biased and incomplete understanding of DC sub-types. In this study, the authors used the HiSeq 2500 System to perform singe-cell sequencing of 2400 individual DCs from blood donors. Their data reveal six human DC sub-types and four monocyte subtypes in human blood. Further, the data reveal a new DC subset that potently activates T cells. The revised taxonomy enabled by this unbiased NGS approach will enable more accurate biological analyses and immune monitoring.

Science 356 2017
Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy.
Davoli T, Uno H, Wooten EC, Elledge SJ
Abstract -

Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8(+) T cells, and increased expression of cell proliferation markers. Different types of SCNAs predict the proliferation and immune signatures, implying distinct underlying mechanisms. Using published data from two clinical trials of immune checkpoint blockade therapy for metastatic melanoma, we found that tumor aneuploidy inversely correlates with patient survival. Together with other tumor characteristics such as tumor mutational load, aneuploidy may thus help identify patients most likely to respond to immunotherapy.

Illumina Summary -

Somatic copy number alterations (SNCAs) are abundant in cancers and have been proposed to drive cancer formation. Immune evasion is a hallmark of cancer, but it is not known to what extent SNCAs may play a role in this process. The authors analyzed approximately 5000 tumor/normal samples form The Cancer Genome Atlas (TCGA) and assigned a SNCA score to each tumor. They found that SCNA levels positively correlated with the total number of mutations for most tumors. Further, tumors with high levels of SNCAs had enhanced expressions of cell proliferation markers and reduced levels of expression of immune cell infiltrate markers. Finally, the authors found that high SNCA levels correlated with poor survival of melanoma patients. The data suggest that cell proliferation and immune evasion in cancer can be predicted by SNCAs, and that SNCA s might be a useful biomarker for predicting response to immunotherapies.

Science 355 2017
Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade.
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA
Abstract -

The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-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 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 MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

Illumina Summary -

Mismatch-repair (MMR) deficient tumors contain many mutation-associated neoantigens (MANAs). The MANAs might be recognized by the host immune system, suggesting the possibility that MMR deficient cancers may be particularly responsive to PD-1 blockade immunotherapy. In this study, the investigators initiated a phase II clinical trial to test the efficacy of PD-1 blockade therapy in different subtypes of MMR deficient cancers. To identify somatic mutations, the authors performed whole-genome sequencing of tumor/normal tissues using the HiSeq 2000/2500 and MiSeq Systems. The authors found that more than half of patients responded well to PD-1 blockade therapy. Further, the authors used additional genomic approaches to identify neoantigen-specific T cell clones that specifically reacted to mutant neopeptides found in these tumors. These data suggest that MMR deficient cancers, regardless of tissue of origin, may be sensitive to immune checkpoint blockade therapy.

Science 2017
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, Bajorin DF, IMvigor210 Study Group
Abstract -

First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.

Lancet 389 67-76 2017
Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.
Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, Zhang T, Adleff V, Phallen J, Wali N, Hruban C, Guthrie VB, Rodgers K, Naidoo J, Kang H, Sharfman W, Georgiades C, Verde F, Illei P, Li QK, Gabrielson E, Brock MV, Zahnow CA, Baylin SB, Scharpf RB, Brahmer JR, Karchin R, Pardoll DM, Velculescu VE
Abstract -

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.SIGNIFICANCE: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 1-13. ©2017 AACR.See related commentary by Yang, p. 250.

Illumina Summary -

Tumor cells contain somatic mutations that alter the amino acid sequence of expressed proteins. These alterations in coding sequence lead to expression of tumor-specific neoantigens that can induce a host immune response against the tumor. Some cancers, especially those expressing PD-L1, respond well to PD-1 blockade therapy. However, cancers can develop resistance to PD-1 blockade. Upregulation of alternate immune checkpoints or somatic mutations have been hypothesized to underlie resistance mechanisms, but the specific mechanisms have not been identified. In this study, the authors used the HiSeq 2000/2500 System to perform whole exome sequencing of non-small cell lung cancer (NSCLC) tumors hat developed resistance to PD-1 blockade. Their work suggests that the acquisition of PD-1 resistance in NSCLC is associated with loss of somatic mutations encoding for NSCLC-specific neoantigens. These data suggest that genomic alterations may be useful in patient-specific immunotherapy approaches.

Cancer Discov 33 1152-8 2016
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C
Abstract -

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.

Science 351 1463-9 2016
Deep sequencing of 10,000 human genomes.
Telenti A, Pierce LC, Biggs WH, di Iulio J, Wong EH, Fabani MM, Kirkness EF, Moustafa A, Shah N, Xie C, Brewerton SC, Bulsara N, Garner C, Metzker G, Sandoval E, Perkins BA, Och FJ, Turpaz Y, Venter JC
Abstract -

We report on the sequencing of 10,545 human genomes at 30×-40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.

Proc Natl Acad Sci U S A 113 11901-11906 2016
Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma.
Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, Bahl S, Cao Y, Amin-Mansour A, Yamauchi M, Sukawa Y, Stewart C, Rosenberg M, Mima K, Inamura K, Nosho K, Nowak JA, Lawrence MS, Giovannucci EL, Chan AT, Ng K, Meyerhardt JA, Van Allen EM, Getz G, Gabriel SB, Lander ES, Wu CJ, Fuchs CS, Ogino S, Garraway LA
Abstract -

Large-scale genomic characterization of tumors from prospective cohort studies may yield new insights into cancer pathogenesis. We performed whole-exome sequencing of 619 incident colorectal cancers (CRCs) and integrated the results with tumor immunity, pathology, and survival data. We identified recurrently mutated genes in CRC, such as BCL9L, RBM10, CTCF, and KLF5, that were not previously appreciated in this disease. Furthermore, we investigated the genomic correlates of immune-cell infiltration and found that higher neoantigen load was positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes (TILs), memory T cells, and CRC-specific survival. The association with TILs was evident even within microsatellite-stable tumors. We also found positive selection of mutations in HLA genes and other components of the antigen-processing machinery in TIL-rich tumors. These results may inform immunotherapeutic approaches in CRC. More generally, this study demonstrates a framework for future integrative molecular epidemiology research in colorectal and other malignancies.

Illumina Summary -

High throughput sequencing approaches for cancer has refined not only understanding of the genomic landscape of cancer, but also understanding immune system regulation of tumorigenesis. In this study, the authors developed a new model for molecular epidemiology research by integrating genomic data with clinical, epidemiological and pathological annotation data linked to colorectal cancer (CRC). Whole exome sequencing (WES) was performed on 619 archived tumor-normal colorectal cancer (CRC) tissue pairs obtained from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), well-known long-term cancer epidemiology studies. They identified recurrent mutations in 90 genes, including 73 new CRC driver genes. Somatic mutations were used to predict immunogenic peptides, and tumors with high neoantigen load were associated with infiltration of lymphocytes and memory T cells as well as improved CRC-specific survival. These results demonstrate an integrated model for genetic epidemiology in cancer and may inform CRC immunotherapeutic approaches.

Cell Rep 16 2016
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.
Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA
Abstract -

We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×10(11) HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.

Illumina Summary -

Tumor-infiltrating lymphocytes (TILs) can be expanded ex vivo and can block tumor growth for some metastatic cancers, likely through T cell recognition of tumor neoantigens. Mutations in the KRAS oncogene are frequent and drive the formation of many cancer types, yet no currently available drugs target oncogenic KRAS. In this study, the authors present clinical and biological data from a single patient with metastatic colorectal cancer. TILs were isolated from tumor tissues, and tested for reactivity against tumor neoepitopes. CD8+ T cells recognizing the KRAS G12D oncogenic variant were identified. The most KRAS G12D reactive CD8+ T cells were expanded and infused into the patient. This adoptive transfer of T cells specifically targeting mutant KRAS G12D led to the regression of metastatic colon cancer in this patient. Tumors that progressed despite treatment were subjected to whole exome and RNA sequencing using the NextSeq 500 System, and these resistant tumors contained additional mutations in the HLA locus. The data suggest that TILs targeting oncogenic KRAS neoantigens may be an effective treatment option for some metastatic cancers, but that additional targeting of HLA neoantigens may also be required for full efficacy.

N Engl J Med 375 2255-2262 2016
Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease.
Mallawaarachchi AC, Hort Y, Cowley MJ, McCabe MJ, Minoche A, Dinger ME, Shine J, Furlong TJ
Abstract -

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder and is due to disease-causing variants in PKD1 or PKD2. Strong genotype-phenotype correlation exists although diagnostic sequencing is not part of routine clinical practice. This is because PKD1 bears 97.7% sequence similarity with six pseudogenes, requiring laborious and error-prone long-range PCR and Sanger sequencing to overcome. We hypothesised that whole-genome sequencing (WGS) would be able to overcome the problem of this sequence homology, because of 150?bp, paired-end reads and avoidance of capture bias that arises from targeted sequencing. We prospectively recruited a cohort of 28 unique pedigrees with ADPKD phenotype. Standard DNA extraction, library preparation and WGS were performed using Illumina HiSeq X and variants were classified following standard guidelines. Molecular diagnosis was made in 24 patients (86%), with 100% variant confirmation by current gold standard of long-range PCR and Sanger sequencing. We demonstrated unique alignment of sequencing reads over the pseudogene-homologous region. In addition to identifying function-affecting single-nucleotide variants and indels, we identified single- and multi-exon deletions affecting PKD1 and PKD2, which would have been challenging to identify using exome sequencing. We report the first use of WGS to diagnose ADPKD. This method overcomes pseudogene homology, provides uniform coverage, detects all variant types in a single test and is less labour-intensive than current techniques. This technique is translatable to a diagnostic setting, allows clinicians to make better-informed management decisions and has implications for other disease groups that are challenged by regions of confounding sequence homology.European Journal of Human Genetics advance online publication, 11 May 2016; doi:10.1038/ejhg.2016.48.

Eur J Hum Genet 6 2016
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.
Tirosh I, Izar B, Prakadan SM, Wadsworth MH, Treacy D, Trombetta JJ, Rotem A, Rodman C, Lian C, Murphy G, Fallahi-Sichani M, Dutton-Regester K, Lin JR, Cohen O, Shah P, Lu D, Genshaft AS, Hughes TK, Ziegler CG, Kazer SW, Gaillard A, Kolb KE, Villani AC, Johannessen CM, Andreev AY, Van Allen EM, Bertagnolli M, Sorger PK, Sullivan RJ, Flaherty KT, Frederick DT, Jané-Valbuena J, Yoon CH, Rozenblatt-Rosen O, Shalek AK, Regev A, Garraway LA
Abstract -

To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

Illumina Summary -

Single-cell sequencing has the potential to inform treatment response and drug resistance by assessing malignant, microenvironmental, and immunologic states within tumors. In this study, the authors applied scRNA-Seq to 4645 single cells (malignant, stromal, immune, and endothelial) isolated from 19 patients with metastatic melanoma. They found that malignant cells within the same tumor displayed transcriptional heterogeneity associated with cell cycle, spatial context, and drug resistance. The same tumor had cells with high expression levels of microphthalmia-associated transcription factor (MITF), as well as cells with low MITF levels and elevated levels of AXL kinase (cells prone to early drug resistance). Infiltrating T-cell analysis revealed exhaustion programs, connection to T-cell activation/expansion, and patient variability. This study demonstrates how single-cell genomics can unravel the cellular ecosystem of tumors, with implications for targeted and immune therapies.

Science 352 189-96 2016
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R
Abstract -

Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population.

Illumina Summary -

The authors describe the results of a phase 2 clinical trial that assessed the efficacy of atezolizumab (a PD-L1 blocking antibody) in urothelial carcinoma patients refractory to platinum-based chemotherapy. They authors found that atezolizumab treatment significantly improved clinically-defined objective response rates. In additional exploratory studies, they demonstrated that tumors with high mutational load were predictive for response to atezolizumab. Further, PD-L1 expression on immune cells correlated with increased response. This study demonstrates that PD-L1 expression on immune cells is a potential biomarker for the selection of patients for treatment with atezolizumab. The study also highlights the importance of mutational load in urothelial carcinoma in cancer immunotherapy outcomes.

Lancet 387 1909-20 2016
Microbiome and Anticancer Immunosurveillance.
Zitvogel L, Ayyoub M, Routy B, Kroemer G
Abstract -

Anticancer immune responses can be considered a desirable form of autoimmunity that may be profoundly shaped by the microbiome. Here, we discuss evidence for the microbiome's influence on anti-tumor immunosurveillance, including those that are indirect and can act at a distance, and we put forward hypotheses regarding mechanisms of how these effects are implemented. These may involve cross-reactivity between microbial and tumor antigens shaping T cell repertoires and/or microbial products stimulating pattern recognition receptors that influence the type and intensity of immune responses. Understanding how the microbiome impacts natural cancer immunosurveillance as well as treatment-induced immune responses will pave the way for more effective therapies and prophylactics.

Cell 165 276-87 2016
Computational genomics tools for dissecting tumour-immune cell interactions.
Hackl H, Charoentong P, Finotello F, Trajanoski Z
Abstract -

Recent breakthroughs in cancer immunotherapy and decreasing costs of high-throughput technologies have sparked intensive research into tumour-immune cell interactions using genomic tools. The wealth of the generated data and the added complexity pose considerable challenges and require computational tools to process, to analyse and to visualize the data. Recently, various tools have been developed and used to mine tumour immunologic and genomic data effectively and to provide novel mechanistic insights. Here, we review computational genomics tools for cancer immunology and provide information on the requirements and functionality in order to assist in the selection of tools and assembly of analytical pipelines.

Illumina Summary -

Cancer immunotherapy research is elucidating checkpoint molecules as targets for drug discovery, and cancer immunotherapy is poised to become a major cancer treatment regimen. However, deep mining of genomics data is critically important for identifying tumor neoantigen landscape and immunophenotypes. Although NGS-based genomics approaches have seen dramatic increases in sequencing throughput over the last few years, appropriate bioinformatics and computational tools for analyzing these large data sets are still lacking. In this review, the authors summarize numerous computational tools for analyzing cancer immunotherapy data from large data sets.

Nat Rev Genet 17 441-58 2016
Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities.
Subudhi SK, Aparicio A, Gao J, Zurita AJ, Araujo JC, Logothetis CJ, Tahir SA, Korivi BR, Slack RS, Vence L, Emerson RO, Yusko E, Vignali M, Robins HS, Sun J, Allison JP, Sharma P
Abstract -

Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor responses in a subset of patients with advanced malignancies, but they may also induce inflammatory responses and toxicities termed immune-related adverse events (irAEs). These irAEs are often low grade and manageable, but severe irAEs may lead to prolonged hospitalizations or fatalities. Early intervention is necessary to minimize morbidities that occur with severe irAEs. However, correlative biomarkers are currently lacking. In a phase II clinical trial that treated 27 patients with metastatic prostate cancer, we aimed to test the safety and efficacy of androgen deprivation therapy plus ipilimumab. In this study, we observed grade 3 toxicities in >40% of treated patients, which led to early closure of the study. Because ipilimumab enhances T-cell responses, we hypothesized that increased clonal T-cell responses in the systemic circulation may contribute to irAEs. Sequencing of the T-cell receptor ß-chains in purified T cells revealed clonal expansion of CD8 T cells, which occurred in blood samples collected before the onset of grade 2-3 irAEs. These initial results suggested that expansion of =55 CD8 T-cell clones preceded the development of severe irAEs. We further evaluated available blood samples from a second trial and determined that patients who experienced grade 2-3 irAEs also had expansion of =55 CD8 T-cell clones in blood samples collected before the onset of irAEs. We propose that CD8 T-cell clonal expansion may be a correlative biomarker to enable close monitoring and early intervention for patients receiving ipilimumab.

Illumina Summary -

Immune checkpoint therapies have made a significant impact on cancer treatment, inducing clinical responses in patients with different types of solid tumors. A complication to immunotherapy is the high incidence of immune-related adverse events (AEs). In some cases, these AEs can be severe, and early intervention can attenuate the severity of some AEs. However, there are currently no biomarkers for detecting or managing these immune-related AEs. In this phase II clinical trial, the authors treated 27 patients with metastatic prostate cancer with androgen deprivation therapy plus ipilimumab, a CTLA-4 blocking antibody. They isolated expanded CD8 T cells from these patients and used T cell receptor sequencing to identify more than 50 specific CD8 T cell clones consistently present in patients that experienced grade 2-3 immune-related AEs. These data suggest that CD8 T cell expansion may serve as a biomarker to enable monitoring and early intervention for patients receiving ipilimumab immunotherapy.

Proc Natl Acad Sci U S A 113 11919-11924 2016