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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:Immune checkpoint blockade (ICB) has become the standard of care for several solid tumors. Multiple combinatorial approaches have been studied to improve therapeutic efficacy. The combination of antiangiogenic agents and ICB has demonstrated efficacy in several cancers. To improve the mechanistic understanding of synergies with these treatment modalities, we performed screens of sera from long-term responding patients treated with ipilimumab and bevacizumab. We discovered a high-titer antibody response against EGF-like repeats and discoidin I-like domains protein 3 (EDIL3) that correlated with favorable clinical outcomes. EDIL3 is an extracellular protein, previously identified as a marker of poor prognosis in various malignancies. Our Tumor Immune Dysfunction and Exclusion analysis predicted that EDIL3 was associated with immune exclusion signatures for cytotoxic immune cell infiltration and nonresponse to ICB. Cancer-associated fibroblasts (CAF) were predicted as the source of EDIL3 in immune exclusion-related cells. Furthermore, The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) and CheckMate 064 data analyses correlated high levels of EDIL3 with increased pan-fibroblast TGFβ response, enrichment of angiogenic signatures, and induction of epithelial-to-mesenchymal transition. Our in vitro studies validated EDIL3 overexpression and TGFβ regulation in patient-derived CAFs. In pretreatment serum samples from patients, circulating levels of EDIL3 were associated with circulating levels of VEGF, and like VEGF, EDIL3 increased the angiogenic abilities of patient-derived tumor endothelial cells (TEC). Mechanistically, three-dimensional microfluidic cultures and two-dimensional transmigration assays with TEC endorsed EDIL3-mediated disruption of the lymphocyte function-associated antigen-1 (LFA-1)-ICAM-1 interaction as a possible means of T-cell exclusion. We propose EDIL3 as a potential target for improving the transendothelial migration of immune cells and efficacy of ICB therapy.

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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