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T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

ABSTRACT: Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

SUBMITTER: Huang AC

PROVIDER: S-EPMC5554367 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

Huang Alexander C AC Postow Michael A MA Orlowski Robert J RJ Mick Rosemarie R Bengsch Bertram B Manne Sasikanth S Xu Wei W Harmon Shannon S Giles Josephine R JR Wenz Brandon B Adamow Matthew M Kuk Deborah D Panageas Katherine S KS Carrera Cristina C Wong Phillip P Quagliarello Felix F Wubbenhorst Bradley B D'Andrea Kurt K Pauken Kristen E KE Herati Ramin S RS Staupe Ryan P RP Schenkel Jason M JM McGettigan Suzanne S Kothari Shawn S George Sangeeth M SM Vonderheide Robert H RH Amaravadi Ravi K RK Karakousis Giorgos C GC Schuchter Lynn M LM Xu Xiaowei X Nathanson Katherine L KL Wolchok Jedd D JD Gangadhar Tara C TC Wherry E John EJ

Nature 20170410 7652

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after tre ...[more]

PMID: 28397821

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Project description:BackgroundWhile mutation-derived neoantigens are well recognized in generating anti-tumour T cell response, increasing evidences highlight the complex association between tumour mutation burden (TMB) and tumour infiltrating lymphocytes (TILs). The exploration of non-TMB determinants of active immune response could improve the prognosis prediction and provide guidance for current immunotherapy.MethodsThe transcriptomic and whole exome sequence data in The Cancer Genome Atlas were used to examine the relationship between TMB and exhausted CD8+ T cells (Tex), as an indicator of tumour antigen-specific T cells across nine major cancer types. Computational clustering analysis was performed on 4510 tumours to identify different immune profiles. NanoString gene expression analysis and single cell RNA-seq analysis using fresh human breast cancer were performed for finding validation.FindingsTMB was found to be poorly correlated with active immune response in various cancer types. Patient clustering analysis revealed a group of tumours with abundant Tex but low TMB. In those tumours, we observed significantly higher expression of the stimulator of interferon genes (STING) signalling. Dendritic cells, particularly those of BATF3+ lineage, were also found to be essential for accumulation of Tex within tumours. Mechanistically, loss of genomic and cellular integrity, marked by decreased DNA damage repair, defective replication stress response, and increased apoptosis were shown to drive STING activation.InterpretationThese results highlight that TMB alone does not fully predict tumour immune profiles, with STING signalling compensating for low TMB in non-hypermutated tumours to enhance anti-tumour immunity. Translating these results, STING agonists may benefit patients with non-hypermutated tumours. STING activation may serve as an additional biomarker to predict response to immune checkpoint blockades alongside TMB. Our research also unravelled the interplay between genomic instability and STING activation, informing potential combined chemotherapy targeting the axis of genomic integrity and immunotherapy.FundingCity of Hope Christopher Family Endowed Innovation Fund for Alzheimer's Disease and Breast Cancer Research in honor of Vineta Christopher; Breast Cancer Alliance Early Career Investigator Award; National Cancer Institute of the National Institutes of Health under award number R01CA256989 and R01CA240392.

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T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

Publications

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

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