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A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.

ABSTRACT: Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.

SUBMITTER: Jerby-Arnon L

PROVIDER: S-EPMC6410377 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.

Jerby-Arnon Livnat L Shah Parin P Cuoco Michael S MS Rodman Christopher C Su Mei-Ju MJ Melms Johannes C JC Leeson Rachel R Kanodia Abhay A Mei Shaolin S Lin Jia-Ren JR Wang Shu S Rabasha Bokang B Liu David D Zhang Gao G Margolais Claire C Ashenberg Orr O Ott Patrick A PA Buchbinder Elizabeth I EI Haq Rizwan R Hodi F Stephen FS Boland Genevieve M GM Sullivan Ryan J RJ Frederick Dennie T DT Miao Benchun B Moll Tabea T Flaherty Keith T KT Herlyn Meenhard M Jenkins Russell W RW Thummalapalli Rohit R Kowalczyk Monika S MS Cañadas Israel I Schilling Bastian B Cartwright Adam N R ANR Luoma Adrienne M AM Malu Shruti S Hwu Patrick P Bernatchez Chantale C Forget Marie-Andrée MA Barbie David A DA Shalek Alex K AK Tirosh Itay I Sorger Peter K PK Wucherpfennig Kai K Van Allen Eliezer M EM Schadendorf Dirk D Johnson Bruce E BE Rotem Asaf A Rozenblatt-Rosen Orit O Garraway Levi A LA Yoon Charles H CH Izar Benjamin B Regev Aviv A

Cell 20181101 4

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion ...[more]

PMID: 30388455

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Project description:BACKGROUND:Resistance to immune checkpoint inhibitors (ICIs) has been linked to local immunosuppression independent of major ICI targets (e.g., PD-1). Clinical experience with response prediction based on PD-L1 expression suggests that other factors influence sensitivity to ICIs in non-small cell lung cancer (NSCLC) patients. METHODS:Tumor specimens from 120 NSCLC patients from 10 institutions were evaluated for PD-L1 expression by immunohistochemistry, and global proliferative profile by targeted RNA-seq. RESULTS:Cell proliferation, derived from the mean expression of 10 proliferation-associated genes (namely BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, and TOP2A), was identified as a marker of response to ICIs in NSCLC. Poorly, moderately, and highly proliferative tumors were somewhat equally represented in NSCLC, with tumors with the highest PD-L1 expression being more frequently moderately proliferative as compared to lesser levels of PD-L1 expression. Proliferation status had an impact on survival in patients with both PD-L1 positive and negative tumors. There was a significant survival advantage for moderately proliferative tumors compared to their combined highly/poorly counterparts (p?=?0.021). Moderately proliferative PD-L1 positive tumors had a median survival of 14.6?months that was almost twice that of PD-L1 negative highly/poorly proliferative at 7.6?months (p?=?0.028). Median survival in moderately proliferative PD-L1 negative tumors at 12.6?months was comparable to that of highly/poorly proliferative PD-L1 positive tumors at 11.5?months, but in both instances less than that of moderately proliferative PD-L1 positive tumors. Similar to survival, proliferation status has impact on disease control (DC) in patients with both PD-L1 positive and negative tumors. Patients with moderately versus those with poorly or highly proliferative tumors have a superior DC rate when combined with any classification schema used to score PD-L1 as a positive result (i.e., TPS???50% or???1%), and best displayed by a DC rate for moderately proliferative tumors of no less than 40% for any classification of PD-L1 as a negative result. While there is an over representation of moderately proliferative tumors as PD-L1 expression increases this does not account for the improved survival or higher disease control rates seen in PD-L1 negative tumors. CONCLUSIONS:Cell proliferation is potentially a new biomarker of response to ICIs in NSCLC and is applicable to PD-L1 negative tumors.

Dataset Information

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.

Publications

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.

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