1019P - Bispecific PD1-IL2 antibody reshapes the inhibitory immune microenvironment of SMARCA4 mutant non-small cell lung cancer by reversing CD8+T cell exhaustion

Background

The efficacy of immune checkpoint inhibitors (ICIs) in SMARCA4 mutant non-small cell lung cancer (NSCLC) is limited. CD8⁺ T cell exhaustion plays an important role in damaging anti-tumor immunity, but the molecular mechanisms remain unclear.

Methods

We compared the survival difference between patients with SMARCA4 mutation and wild type. The RNA sequencing of CD8+T cells sorted from tumor tissues was performed. The SMARCA4 mutant-H1299 cells were implanted into the left flank of the NSG mice. 2×107 human PBMCs were separated and injected intravenously into NSG mice to establish humanized NSG mouse models. Anti-PD-1 of Bispecific PD1-IL2 antibody were given intraperitoneally. The frequencies and phenotypes of CD8⁺T cells in mouse spleens and blood were detected by flow cytometry while those in tumor tissues were determined by multiplex immunofluorescence (mIF). The mIF staining was performed to validate differences of CD8⁺ T cells exhaustion phenotype between SMARCA4 mutant and wild-type patient tissues.

Results

Treatment with ICIs could not improve outcomes in patients with SMARCA4 mutations (P = 0.754). The analysis of RNA sequencing showed that the production of interleukin-2 (IL-2) was significantly reduced in CD8⁺T cells of SMARCA4 mutant Lewis lung carcinoma (P < 0.001). The analysis of mIF revealed that the infiltration of PD1⁺CD8⁺, LAG3⁺CD8⁺, TIM3⁺CD8⁺ T cells increased in SMARCA4 mutant tumor tissues. We found that a high level of IL-2 leads to the persistent activation of STAT5 in CD8⁺ T cells. Bispecific PD1-IL2 antibody enhanced anti-tumor immunity and suppressed tumor progression by reversing CD8⁺T cells exhaustion.

Conclusions

The PD1-IL2 bispecific antibody could reverse CD8⁺T cell exhaustion to enhance anti-tumor immunity in SMARCA4 mutant NSCLC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

H. Wang.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.