Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

Christina Twyman-Saint Victor; Andrew J Rech; Amit Maity; Ramesh Rengan; Kristen E Pauken; Erietta Stelekati; Joseph L Benci; Bihui Xu; Hannah Dada; Pamela M Odorizzi; Ramin S Herati; Kathleen D Mansfield; Dana Patsch; Ravi K Amaravadi; Lynn M Schuchter; Hemant Ishwaran; Rosemarie Mick; Daniel A Pryma; Xiaowei Xu; Michael D Feldman; Tara C Gangadhar; Stephen M Hahn; E John Wherry; Robert H Vonderheide; Andy J Minn

doi:10.1038/nature14292

Back

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

Journal article

Open access

Peer reviewed

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

Christina Twyman-Saint Victor, Andrew J Rech, Amit Maity, Ramesh Rengan, Kristen E Pauken, Erietta Stelekati, Joseph L Benci, Bihui Xu, Hannah Dada, Pamela M Odorizzi, …

Nature (London), Vol.520(7547), pp.373-377

2015-04-16

DOI: https://doi.org/10.1038/nature14292

PMID: 25754329

Abstract

Receptors, Antigen, T-Cell - metabolism

Humans

Mice, Inbred C57BL

Melanoma - radiotherapy

T-Lymphocytes - radiation effects

Melanoma - pathology

T-Lymphocytes, Regulatory - immunology

T-Lymphocytes, Regulatory - radiation effects

Receptors, Antigen, T-Cell - drug effects

B7-H1 Antigen - metabolism

T-Lymphocytes, Regulatory - drug effects

Animals

B7-H1 Antigen - antagonists & inhibitors

T-Lymphocytes - cytology

Cell Cycle Checkpoints - drug effects

Melanoma - immunology

T-Lymphocytes - drug effects

Melanoma - drug therapy

Female

Receptors, Antigen, T-Cell - immunology

T-Lymphocytes - immunology

Mice

Mice, Inbred BALB C

CTLA-4 Antigen - antagonists & inhibitors

Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.

Files and links (1)

url

https://doi.org/10.1038/nature14292View

Published (Version of record) Open

Metrics

60 Record Views

1758 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Highly Cited Paper

Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.6 Immunology; 1.6.214 PD-1
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer
Creators: Christina Twyman-Saint Victor - 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Andrew J Rech - Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Amit Maity - 1] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Ramesh Rengan - 1] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Kristen E Pauken - 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Erietta Stelekati - 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Joseph L Benci - 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Bihui Xu - 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Hannah Dada - 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Pamela M Odorizzi - 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Ramin S Herati - 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Kathleen D Mansfield - 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Dana Patsch - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Ravi K Amaravadi - 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Lynn M Schuchter - 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Hemant Ishwaran - Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, Florida 33136, USA
Rosemarie Mick - 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Daniel A Pryma - 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Xiaowei Xu - 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Michael D Feldman - 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Tara C Gangadhar - 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Stephen M Hahn - 1] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
E John Wherry - 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Robert H Vonderheide - 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Andy J Minn - 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Publication Details: Nature (London), Vol.520(7547), pp.373-377
Publisher: England
Grant note: P01 AI112521 / NIAID NIH HHS U01AI095608 / NIAID NIH HHS U19 AI082630 / NIAID NIH HHS R01 AI105343 / NIAID NIH HHS T32 DK007066 / NIDDK NIH HHS KL2 TR000139 / NCATS NIH HHS R01 CA169123 / NCI NIH HHS R01 CA172651 / NCI NIH HHS P30CA016520 / NCI NIH HHS UL1 RR024134 / NCRR NIH HHS KL2TR000139 / NCATS NIH HHS R01AI105343 / NIAID NIH HHS UL1RR024134 / NCRR NIH HHS R01CA172651 / NCI NIH HHS R01CA163739 / NCI NIH HHS P30 CA016520 / NCI NIH HHS R01 CA169134 / NCI NIH HHS P50CA174523 / NCI NIH HHS U01 AI095608 / NIAID NIH HHS T32DK007066 / NIDDK NIH HHS P01AI112521 / NIAID NIH HHS R01CA158186 / NCI NIH HHS P50 CA174523 / NCI NIH HHS R01 CA163739 / NCI NIH HHS R01 CA158186 / NCI NIH HHS U19AI082630 / NIAID NIH HHS
Academic Unit: Miller School of Medicine; Microbiology and Immunology Research; UMMG Department of Public Health Sciences Research
Language: English
Resource Type: Journal article
PMID: 25754329
Record Identifier: 991031559411902976