Development and Performance of a CD8 Gene Signature for Characterizing Inflammation in the Tumor Microenvironment Across Multiple Tumor Types

IntroductionImmune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) axis have demonstrated significant clinical benefit across a range of tumor types.Büttner R. Longshore J.W. Lopez-Rios F. Merkelbach-Bruse S. Normanno N. Rouleau E. Penault-Llorca F. Implementing TMB measurement in clinical practice: considerations on assay requirements. There is, however, a critical need to identify subsets of patients who are likely to respond to ICIs or alternative therapies.Chan T.A. Yarchoan M. Jaffee E. Swanton C. Quezada S.A. Stenzinger A. Peters S. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Precision medicine is an emerging approach for guiding treatment for patients with cancer, considering the molecular and genomic variability between tumors.Malone E.R. Oliva M. Sabatini P.J.B. Stockley T.L. Siu L.L. Molecular profiling for precision cancer therapies. Various genomic, transcriptomic, and proteomic methods have been developed to interrogate the tumor microenvironment (TME) to identify biomarkers for selecting those patients who are likely to respond to a particular therapy. These biomarkers are being investigated, alone and in combination, to comprehensively assess tumor characteristics that contribute to our understanding of tumor biology and can lead to an improved ability to diagnose, treat, and prevent cancer.Cristescu R. Mogg R. Ayers M. Albright A. Murphy E. Yearley J. Sher X. Liu X.Q. Lu H. Nebozhyn M. Zhang C. Lunceford J.K. Joe A. Cheng J. Webber A.L. Ibrahim N. Plimack E.R. Ott P.A. Seiwert T.Y. Ribas A. Mcclanahan T.K. Tomassini J.E. Loboda A. Kaufman D. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.Ayers M. Lunceford J. Nebozhyn M. Murphy E. Loboda A. Kaufman D.R. Albright A. Cheng J.D. Kang S.P. Shankaran V. Piha-Paul S.A. Yearley J. Seiwert T.Y. Ribas A. McClanahan T.K. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade.Tsao M.S. Kerr K.M. Kockx M. Beasley M.B. Borczuk A.C. Botling J. Bubendorf L. Chirieac L. Chen G. Chou T.-Y. Chung J.-H. Dacic S. Lantuejoul S. Mino-Kenudson M. Moreira A.L. Nicholson A.G. Noguchi M. Pelosi G. Poleri C. Russell P.A. Sauter J. Thunnissen E. Wistuba I. Yu H. Wynes M.W. Pintilie M. Yatabe Y. Hirsch F.R. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of Blueprint phase 2 project.Socinski M.A. Jotte R.M. Cappuzzo F. Orlandi F. Stroyakovskiy D. Nogami N. Rodríguez-Abreu D. Moro-Sibilot D. Thomas C.A. Barlesi F. Finley G. Kelsch C. Lee A. Coleman S. Deng Y. Shen Y. Kowanetz M. Lopez-Chavez A. Sandler A. Reck M. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.Le D.T. Uram J.N. Wang H. Bartlett B.R. Kemberling H. Eyring A.D. Skora A.D. Luber B.S. Azad N.S. Laheru D. Biedrzycki B. Donehower R.C. Zaheer A. Fisher G.A. Crocenzi T.S. Lee J.J. Duffy S.M. Goldberg R.M. de la Chapelle A. Koshiji M. Bhaijee F. Huebner T. Hruban R.H. Wood L.D. Cuka N. Pardoll D.M. Papadopoulos N. Kinzler K.W. Zhou S. Cornish T.C. Taube J.M. Anders R.A. Eshleman J.R. Vogelstein B. Diaz L.A.J. PD-1 blockade in tumors with mismatch-repair deficiency.Riaz N. Havel J.J. Makarov V. Desrichard A. Urba W.J. Sims J.S. Hodi F.S. Martin-Algarra S. Mandal R. Sharfman W.H. Bhatia S. Hwu W.-J. Gajewski T.F. Slingluff Jr., C.L. Chowell D. Kendall S.M. Chang H. Shah R. Kuo F. Morris L.G.T. Sidhom J.-W. Schneck J.P. Horak C.E. Weinhold N. Chan T.A. Tumor and microenvironment evolution during immunotherapy with nivolumab.Rizvi N.A. Hellmann M.D. Snyder A. Kvistborg P. Makarov V. Havel J.J. Lee W. Yuan J. Wong P. Ho T.S. Miller M.L. Rekhtman N. Moreira A.L. Ibrahim F. Bruggeman C. Gasmi B. Zappasodi R. Maeda Y. Sander C. Garon E.B. Merghoub T. Wolchok J.D. Schumacher T.N. Chan T.A. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.The Cancer Genome Atlas: creating lasting value beyond its data.A T-cell–inflamed phenotype in the tumor microenvironment (TME) has been associated with improved clinical efficacy in patients treated with immuno-oncology (I-O) therapy,Darvin P. Toor S.M. Sasidharan Nair V. Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers.Tumeh P.C. Harview C.L. Yearley J.H. Shintaku I.P. Taylor E.J.M. Robert L. Chmielowski B. Spasic M. Henry G. Ciobanu V. West A.N. Carmona M. Kivork C. Seja E. Cherry G. Gutierrez A.J. Grogan T.R. Mateus C. Tomasic G. Glaspy J.A. Emerson R.O. Robins H. Pierce R.H. Elashoff D.A. Robert C. Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance.Spranger S. Spaapen R.M. Zha Y. Williams J. Meng Y. Ha T.T. Gajewski T.F. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. and inflammation biomarkers are currently being investigated, alone and in combination, for associations with the clinical efficacy of ICIs across multiple tumor types.Carbone D.P. Reck M. Paz-Ares L. Creelan B. Horn L. Steins M. Felip E. van den Heuvel M.M. Ciuleanu T.-E. Badin F. Ready N. Hiltermann T.J.N. Nair S. Juergens R. Peters S. Minenza E. Wrangle J.M. Rodriguez-Abreu D. Borghaei H. Blumenschein Jr., G.R. Villaruz L.C. Havel L. Krejci J. Corral Jaime J. Chang H. Geese W.J. Bhagavatheeswaran P. Chen A.C. Socinski M.A. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.Fuchs C.S. Doi T. Jang R.W. Muro K. Satoh T. Machado M. Sun W. Jalal S.I. Shah M.A. Metges J.-P. Garrido M. Golan T. Mandala M. Wainberg Z.A. Catenacci D.V. Ohtsu A. Shitara K. Geva R. Bleeker J. Ko A.H. Ku G. Philip P. Enzinger P.C. Bang Y.-J. Levitan D. Wang J. Rosales M. Dalal R.P. Yoon H.H. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.Schmid P. Adams S. Rugo H.S. Schneeweiss A. Barrios C.H. Iwata H. Dieras V. Hegg R. Im S.-A. Shaw Wright G. Henschel V. Molinero L. Chui S.Y. Funke R. Husain A. Winer E.P. Loi S. Emens L.A. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.Büttner R. Gosney J.R. Skov B.G. Adam J. Motoi N. Bloom K.J. Dietel M. Longshore J.W. Lopez-Rios F. Penault-Llorca F. Viale G. Wotherspoon A.C. Kerr K.M. Tsao M.-S. Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. CD8+ tumor-infiltrating immune cells, often assessed using immunohistochemistry (IHC), can be used as a surrogate marker for inflammation that is associated with improved prognosis in a broad range of tumor types.Stoll G. Bindea G. Mlecnik B. Galon J. Zitvogel L. Kroemer G. Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies.HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer.Chen J. He Q. Liu J. Xiao Y. Xiao C. Chen K. Xie D. Zhang X. CD8+ tumor-infiltrating lymphocytes as a novel prognostic biomarker in lung sarcomatoid carcinoma, a rare subtype of lung cancer. PD-L1 expression, determined on either tumor cells, immune cells, or both, may be indicative of a pre-existing immunologically active TME, and increased clinical efficacy of ICIs in patients with PD-L1–positive tumors has led to the approval of a number of PD-L1 IHC companion and complementary diagnostic assays for various tumor types.Krigsfeld G.S. Prince E.A. Pratt J. Chizhevsky V. Ragheb J.W. Novotny Jr., J. Huron D. Analysis of real-world PD-L1 IHC 28-8 and 22C3 pharmDx assay utilisation, turnaround times and analytical concordance across multiple tumour types. In addition to biomarkers of inflammation, tumor characteristics that correlate with neoantigen load are being investigated as surrogates for potential antitumor immune responses. Mismatch repair deficiency (dMMR) determined using IHC, microsatellite instability (MSI) determined using polymerase chain reaction (PCR), and tumor mutational burden (TMB) determined by next-generation sequencing (NGS) have each been associated with improved clinical efficacy of ICIs across a number of tumor types.Le D.T. Uram J.N. Wang H. Bartlett B.R. Kemberling H. Eyring A.D. Skora A.D. Luber B.S. Azad N.S. Laheru D. Biedrzycki B. Donehower R.C. Zaheer A. Fisher G.A. Crocenzi T.S. Lee J.J. Duffy S.M. Goldberg R.M. de la Chapelle A. Koshiji M. Bhaijee F. Huebner T. Hruban R.H. Wood L.D. Cuka N. Pardoll D.M. Papadopoulos N. Kinzler K.W. Zhou S. Cornish T.C. Taube J.M. Anders R.A. Eshleman J.R. Vogelstein B. Diaz L.A.J. PD-1 blockade in tumors with mismatch-repair deficiency.,Riaz N. Havel J.J. Makarov V. Desrichard A. Urba W.J. Sims J.S. Hodi F.S. Martin-Algarra S. Mandal R. Sharfman W.H. Bhatia S. Hwu W.-J. Gajewski T.F. Slingluff Jr., C.L. Chowell D. Kendall S.M. Chang H. Shah R. Kuo F. Morris L.G.T. Sidhom J.-W. Schneck J.P. Horak C.E. Weinhold N. Chan T.A. Tumor and microenvironment evolution during immunotherapy with nivolumab.,Buecher B. Cacheux W. Rouleau E. Dieumegard B. Mitry E. Lievre A. Role of microsatellite instability in the management of colorectal cancers.Hellmann M.D. Callahan M.K. Awad M.M. Calvo E. Ascierto P.A. Atmaca A. Rizvi N.A. Hirsch F.R. Selvaggi G. Szustakowski J.D. Sasson A. Golhar R. Vitazka P. Chang H. Geese W.J. Antonia S.J. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer.Hellmann M.D. Ciuleanu T.-E. Pluzanski A. Lee J.S. Otterson G.A. Audigier-Valette C. Minenza E. Linardou H. Burgers S. Salman P. Borghaei H. Ramalingam S.S. Brahmer J. Reck M. O’Byrne K.J. Geese W.J. Green G. Chang H. Szustakowski J. Bhagavatheeswaran P. Healey D. Fu Y. Nathan F. Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.Marabelle A. Le D.T. Ascierto P.A. Giacomo A.M.D. Jesus-Acosta A.D. Delord J.-P. Geva R. Gottfried M. Penel N. Hansen A.R. Piha-Paul S.A. Doi T. Gao B. Chung H.C. Lopez-Martin J. Bang Y.-J. Frommer R.S. Shah M. Ghori R. Joe A.K. Pruitt Jr., S.K. LAD: Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study.Marabelle A. Fakih M. Lopez J. Shah M. Shapira-Frommer R. Nakagawa K. Chung H.C. Kindler H.L. Lopez-Martin J.A. Miller Jr., W.H. Italiano A. Kao S. Piha-Paul S.A. Delord J.P. McWilliams R.R. Fabrizio D.A. Aurora-Garg D. Xu L. Jin F. Norwood K. Bang Y.J. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.Assay methods such as IHC or PCR have limited capability to simultaneously interrogate multiple biomarkers. In contrast, NGS-based gene panel assays offer the potential to characterize genetic or transcriptomic features of large numbers of genes with a single assay.Büttner R. Longshore J.W. Lopez-Rios F. Merkelbach-Bruse S. Normanno N. Rouleau E. Penault-Llorca F. Implementing TMB measurement in clinical practice: considerations on assay requirements.,Ayers M. Lunceford J. Nebozhyn M. Murphy E. Loboda A. Kaufman D.R. Albright A. Cheng J.D. Kang S.P. Shankaran V. Piha-Paul S.A. Yearley J. Seiwert T.Y. Ribas A. McClanahan T.K. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade.,Qi Z. Wang L. Desai K. Cogswell J. Stern M. Lawson B. Kerkar S.P. Vitazka P. Reliable gene expression profiling from small and hematoxylin and eosin–stained clinical formalin-fixed, paraffin-embedded specimens using the HTG EdgeSeq platform. Various gene panel assays are approved for profiling tumor DNA for multiple genomic characteristics in parallel, including MSI, TMB, and gene-specific actionable mutations.Büttner R. Longshore J.W. Lopez-Rios F. Merkelbach-Bruse S. Normanno N. Rouleau E. Penault-Llorca F. Implementing TMB measurement in clinical practice: considerations on assay requirements.,Marabelle A. Fakih M. Lopez J. Shah M. Shapira-Frommer R. Nakagawa K. Chung H.C. Kindler H.L. Lopez-Martin J.A. Miller Jr., W.H. Italiano A. Kao S. Piha-Paul S.A. Delord J.P. McWilliams R.R. Fabrizio D.A. Aurora-Garg D. Xu L. Jin F. Norwood K. Bang Y.J. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.,Stenzinger A. Allen J.D. Maas J. Stewart M.D. Merino D.M. Wempe M.M. Dietel M. Tumor mutational burden (TMB) standardization initiatives: recommendations for consistent TMB assessment in clinical samples to guide immunotherapy treatment decisions. Gene expression profiling (GEP) panels have also been used to analyze the transcriptomes of multiple tumor types and derive gene expression signatures indicative of specific tumor characteristics.Cristescu R. Mogg R. Ayers M. Albright A. Murphy E. Yearley J. Sher X. Liu X.Q. Lu H. Nebozhyn M. Zhang C. Lunceford J.K. Joe A. Cheng J. Webber A.L. Ibrahim N. Plimack E.R. Ott P.A. Seiwert T.Y. Ribas A. Mcclanahan T.K. Tomassini J.E. Loboda A. Kaufman D. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.,Ayers M. Lunceford J. Nebozhyn M. Murphy E. Loboda A. Kaufman D.R. Albright A. Cheng J.D. Kang S.P. Shankaran V. Piha-Paul S.A. Yearley J. Seiwert T.Y. Ribas A. McClanahan T.K. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade.,Sharma P. Retz M. Siefker-Radtke A. Baron A. Necchi A. Bedke J. Plimack E.R. Vaena D. Grimm M.-O. Bracarda S. Arranz J.A. Pal S. Ohyama C. Saci A. Qu X. Lambert A. Krishnan S. Azrilevich A. Galsky M.D. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial.Wang L. Saci A. Szabo P.M. Chasalow S.D. Castillo-Martin M. Domingo-Domenech J. Siefker-Radtke A. Sharma P. Sfakianos J.P. Gong Y. Dominguez-Andres A. Oh W.K. Mulholland D. Azrilevich A. Hu L. Cordon-Cardo C. Salmon H. Bhardwaj N. Zhu J. Galsky M.D. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer.Danaher P. Warren S. Dennis L. D'Amico L. White A. Disis M.L. Geller M.A. Odunsi K. Beechem J. Fling S.P. Gene expression markers of tumor infiltrating leukocytes. For example, GEP panel assays such as Oncotype DX, Prosigna, and MammaPrint have been developed to assess risk of recurrence and guide treatment decisions for patients with breast cancer.The analytical validation of the Oncotype DX Recurrence Score assay.Nielsen T. Wallden B. Schaper C. Ferree S. Liu S. Gao D. Barry G. Dowidar N. Maysuria M. Storhoff J. Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens.Dubsky P. Van't Veer L. Gnant M. Rudas M. Bago-Horvath Z. Greil R. Lujinovic E. Buresch J. Rinnerthaler G. Hulla W. Moinfar F. Egle D. Herz W. Dreezen C. Frantal S. Filipits M. A clinical validation study of MammaPrint in hormone receptor-positive breast cancer from the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) biomarker cohort. Panel-derived signatures indicative of inflammation in the TME have been associated with response to ICIs in multiple tumor types.Cristescu R. Mogg R. Ayers M. Albright A. Murphy E. Yearley J. Sher X. Liu X.Q. Lu H. Nebozhyn M. Zhang C. Lunceford J.K. Joe A. Cheng J. Webber A.L. Ibrahim N. Plimack E.R. Ott P.A. Seiwert T.Y. Ribas A. Mcclanahan T.K. Tomassini J.E. Loboda A. Kaufman D. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.,Danaher P. Warren S. Lu R. Samayoa J. Sullivan A. Pekker I. Wallden B. Marincola F.M. Cesano A. Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA). Other studies have identified interferon gamma (IFNγ)–related signatures that positively associated with response to ICIs,Ayers M. Lunceford J. Nebozhyn M. Murphy E. Loboda A. Kaufman D.R. Albright A. Cheng J.D. Kang S.P. Shankaran V. Piha-Paul S.A. Yearley J. Seiwert T.Y. Ribas A. McClanahan T.K. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade.,Sharma P. Retz M. Siefker-Radtke A. Baron A. Necchi A. Bedke J. Plimack E.R. Vaena D. Grimm M.-O. Bracarda S. Arranz J.A. Pal S.

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