LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8⁺ T cells for improving anti-PD-1 antibody therapy

ABSTRACT

Anti-PD-1 antibody therapy has achieved success in tumor treatment; however, the duration of its clinical benefits are typically short. The functional state of intratumoral CD8⁺ T cells substantially affects the efficacy of anti-PD-1 antibody therapy. Understanding how intratumoral CD8⁺ T cells change will contribute to the improvement in anti-PD-1 antibody therapy. In this study, we found that tumor growth was not arrested after the late administration of anti-PD-1 antibody and that the antitumor function of CD8⁺ T cells decreased with tumor progression. The results of the RNA sequencing of CD8⁺ T cells infiltrating the tumor site on days 7 and 14 showed that the cell adhesion molecule Lymphocyte Function-associated Antigen-1 (LFA-1) participates in regulating the antitumor function of CD8⁺ T cells and that decreased LFA-1 expression in intratumoral CD8⁺ T cells is associated with tumor progression. By analyzing the Gene Expression Omnibus (GEO) database and our results, we found that the antitumor function of intratumoral CD8⁺ T cells with high LFA-1 expression was stronger. The formation of immune synapses is impaired in Itgal-si CD8⁺ T cells, resulting in decreased anti-tumor function. LFA-1 expression in intratumoral CD8⁺ T cells is regulated by the IL-2/STAT5 pathway. The combination of IL-2 and anti-PD-1 antibody effectively enhanced LFA-1 expression and the antitumor function of intratumoral CD8⁺ T cells. The adoptive transfer of OT-1 T cells overexpressing LFA-1, STAT5A, or STAT5B resulted in higher antitumor function, deferred tumor growth, and prolonged survival. These findings indicate that LFA-1-mediated immune synapse acts as a regulator of the antitumor function of intratumoral CD8⁺ T cells, which can be applied to improve anti-PD-1 antibody therapy.

KEYWORDS:

• CD8⁺ T cells
• LFA-1
• immune synapse
• IL-2
• anti-tumor function
• Anti-PD-1 antibody

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The date supporting the finding of this study are available from the corresponding author upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2293511.

Additional information

Funding

This work was supported by the National Key “Research and Development” Program: Intergovernmental International Science and Technology Innovation Cooperation Project (grant nos. 2022YFE0141000), National Natural Science Foundation of China (grant nos. 82272873 and 82102869), the Central Government of Henan Province Guides Local Science and Technology Development Fund Projects (Z20221343036), Medical Science and Technology Project of Henan Province (grant no. SBGJ202101010), and Major Public Welfare Projects in Henan Province (grant No. 201300310400). We thank Henan Key Laboratory for Pharmacology of Liver Diseases for assistance with animal experiments.