29P - Targeting CXCR4 promotes antitumor immunity through TOX-mediated CD8+ T cell activation

Background

Although CXC chemokine receptor 4 (CXCR4) blockades have facilitated antitumor in many cancer types, the mechanisms of CXCR4 blockades underlying antitumor activity, especially in immunity, remain to be determined.

Methods

Single-cell transcriptome data of multi-tissues and T cells of multi-cancers were analyzed to identify the expression patterns of CXCR4 in exhausted CD8⁺ T cells. In addition, in vitro and in vivo assays were used to explore the effects of CXCR4 blockades in promoting anti-PD-1 immunotherapy via JAK2/STAT3/TOX axis of exhausted CD8⁺ T cells.

Results

Single-cell transcriptome analysis of multi-tissues and multi-cancers demonstrated that CXCR4 was a specific marker of T cells, and it was highly expressed in PD-1⁺ exhausted CD8⁺ T cells. By targeting CXCR4, the expressions of TOX and PD-1 was down-regulated, with the upregulation of p-JAK2/p-STAT3 in T cells. Importantly, TOX-mediated CD8⁺ T cell activation of CXCR4 blockades was reversed via the p-JAK2/p-STAT3 inhibitor. In vivo, single-cell transcriptome analysis revealed CXCR4 blockades promotes anti-PD-1 immunotherapy of cervical cancer, breast cancer, and ovarian cancer via activating exhausted CD8⁺ T cells.

Conclusions

Overall, we found that targeting CXCR4 promotes antitumor immunity through TOX-mediated CD8⁺ T cell activation, which paves the way toward immunotherapy in antitumor activity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Key R&D Program of China (2021YFC2701201), National Natural Science Foundation of China (82072895 and 82141106), Shenzhen Science and Technology Innovation Committee (JCYJ20210324105808022, RCBS20210706092345027), China Postdoctoral Science Foundation (2021M702223).

Disclosure

All authors have declared no conflicts of interest.