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 3

Efflux of chemotherapy drug by human CX3CR1+CD8+ T cells.

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Efflux of chemotherapy drug by human CX3CR1+CD8+ T cells. Purified human...
Purified human primary CD8+ T cells were loaded with Doxorubicin (1 μg/ml) for 30 minutes and then washed before further incubation for 60 minutes (A) or at indicated times (B). Gated areas in A are efflux cells (DoxloCX3CR1hi). The data was analyzed by 1-way ANOVA (*P < 0.05, **P < 0.01, n = 6). (C) CD8+ T cells were incubated with Doxorubicin (0.5 μg /ml) for 40 hours and then stained with annexin V to identify apoptotic cells. (D) Expression of ABCB1 by CX3CR1+ or CX3CR1– CD8+ T cells. (E) ABCB1 inhibitor (PGP4008) reduced the drug efflux ability of CX3CR1+CD8+ T cells. Cells incubated on ice after loading with drug were used as a negative control for drug efflux. Data was analyzed by 1-way ANOVA (*P < 0.05, **P < 0.01, n = 7). (F) ABCB1 inhibitor (PGP4008) increased the apoptosis of CX3CR1+CD8+ T cells as cultured in C. The impact of ABCB1 inhibitor on the function of human CX3CR1+CD8+ T cells incubated with (G) or without (H) chemotherapy drug (carboplatin and paclitaxel). CD8+ T cells were activated with anti-CD3/CD28 beads for 24 hours in the presence of DMSO (control) or PGP4008 (10 μM). The CTL function was measured for CD107a expression and IFN-γ production at the end of culture. The data of C–D and F–H were analyzed by Mann-Whitney U test, 2-tailed (*P < 0.05; **P < 0.01, n = 5–7).