Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer

By Christina Twyman-Saint Victor, A. Rech, A. Maity, Ramesh Rengan, Kristen E. Pauken, Erietta Stelekati, Joseph L. Benci, Bihui Xu, Hannah Dada, P. Odorizzi and 15 more. Nature, 2015

2,301 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/50e86518d8b8cfd4d46304046a601048180c4adb

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In Immunology

1. Kristen E. Pauken
2. W. Zou
3. Ilona Kryczek
4. E. Wherry
5. Shuang Wei
6. S. Evers
7. P. Hegde
8. R. Vonderheide

In Oncology

1. Kristen E. Pauken
2. W. Zou
3. S. Evers
4. P. Hegde
5. V. Karanikas
6. E. Wherry
7. Lieping Chen
8. A. Schietinger

Citations in the corpus

• Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells (2016, background): “Recent experimental evidence shows that anti-CTLA-4 mAb efficacy depends on FcgR-mediated depletion of CD4+ regulatory T cells (Treg cells) within the tumor microenvironment (Peggs et al., 2009; Selby et al., 2013; Simpson et al., 2013; TwymanSaint Victor et al., 2015).”
• Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11 (2019, background): “Radiotherapy and Immunotherapy Synergistically Induce Tumoral Ferroptosis Immunotherapy augments radiotherapy efficacy in vivo, but the mechanisms through which immune checkpoint blockade enhances tumor-cell death in irradiated lesions are not well defined (4, 32, 33).”
• Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022, background): “However, the efficacy of CAR-T cell therapy is modest in most solid tumors, which is partly attributed to the immunosuppressive TME [340]. α-PD-1/PD-L1 enhanced CAR-T cell therapy by rescuing CAR-T cell exhaustion [341–343].”
• Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, positive): “The clinical trial of RT and anti-CTLA4 for metastatic melanoma patients (NCT01497808) has been described in detail (Twyman-Saint Victor et al., 2015).”
• The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition (2016, background): “This mechanism of resistance postulates a triple combination of radiotherapy with anti–CTLA-4 and a PD-L1/PD-1 inhibitor to overcome T-cell exhaustion and promote clonal expansion of T cells (45).”