CX3CR1 identifies PD-1 therapy–responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy
Yiyi Yan, … , Roxana S. Dronca, Haidong Dong
Yiyi Yan, … , Roxana S. Dronca, Haidong Dong
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e97828. https://doi.org/10.1172/jci.insight.97828.
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Research Article Immunology Oncology

CX3CR1 identifies PD-1 therapy–responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy

Abstract

Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti–PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy–responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.

Authors

Yiyi Yan, Siyu Cao, Xin Liu, Susan M. Harrington, Wendy E. Bindeman, Alex A. Adjei, Jin Sung Jang, Jin Jen, Ying Li, Pritha Chanana, Aaron S. Mansfield, Sean S. Park, Svetomir N. Markovic, Roxana S. Dronca, Haidong Dong

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Figure 1

CX3CR1+Granzyme B+CD8+ T cells in responders to PD-1 therapy.

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CX3CR1+Granzyme B+CD8+ T cells in responders to PD-1 therapy. RNA was is...
RNA was isolated from CD11ahiCD8+ T cells in the peripheral blood of melanoma patients prior to (A) or after (B) anti–PD-1 therapy. (A) RNA-seq data show an increased transcription of CX3CR1 (arrow) and TCRVβ29-1 (arrow head) in the responders (R, n = 3) compared with the nonresponders (NR, n = 3) at baseline prior to anti–PD-1 therapy. Data represent the average levels of transcription of 3 patients (with at least 1.5-fold changes). (B) RNA-seq data show increased transcriptions of CX3CR1, CD122 (IL2RB), KLRG1, perforin (PRF1), granzyme B (GZMB) (arrows), and TCRVα5/TCRVβ4-2 (arrow heads) on week 12 after PD-1 therapy. Data represent the average levels of transcription of 3 or 2 patients (R, n = 3; NR, n = 2) with at least 2-fold changes. (C) PD-1 expression by CX3CR1+CD11ahi or CX3CR1–CD11alo CD8+ T cells isolated from the peripheral blood of patients with metastatic melanoma prior to PD-1 therapy (n = 12, ***P < 0.01, paired 2-tailed t test). (D) The frequency of CX3CR1+Granzyme B+ cells among CD11ahiCD8+ T cells significantly increased in responders after anti–PD-1 therapy in melanoma patients (n = 7, **P < 0.05, Mann-Whitney U test) but not at baseline prior to PD-1 therapy. (E) Tissue staining of CX3CR1+Granzyme B+ (double-positive staining, DP) in human melanoma tissues. Original magnification ×400. One DP cell was inside the tumor bed (red arrow) and another adhered to a blood vessel, probably in a process of extravasation (yellow arrow).