Presentation Authors: John Sfakianos*, Adam Farkas, Jorge Daza, Harry Anastos, Matthew Galsky, Nina Bhardwaj, New York, NY
Introduction: The introduction of immune checkpoint inhibition with PD-1/PDL-1 blockade represents a paradigm shift in the clinical management of patients with bladder cancer (BCa). However, only 20-30% of patients will respond to therapy, highlighting the importance of identifying novel checkpoint molecules, which may further promote anti-tumor immunity in patients with bladder cancer.
Methods: After IRB approval, PBMC from 45 patients ( non-muscle invasive (NMI), n=29, muscle invasive (MI), n=16, healthy donors (HD)=17) and tumors from 29 patients (NMI, n=13, MI, n=16) were analyzed. Cells were stained with a 14 color FACS panel to identify immune subsets and exhaustion markers (PD-1, TIM-3 and TIGIT). Data was analyzed with FlowJo and Prism.
Results: A diagnosis of BCa, compared to healthy donors, drove maturation of NK cells in PBMC, by increasing the frequency of CD56dimCD16+ cells, while, in tumor tissue, , there was a significant increase in the frequency of immature, CD56brightCD16- NK cells. The mean frequency of PD-1 expression by tumor-resident T cells was 16-25%, (CD4:18-25/%, NMI/MI and CD8 16-25%, NMI/MI), correlating with the published response rates of PD-1 blockade. Mean Tim-3 expression on TIL NK, CD4, and CD8 T cells increased with stage; 15%, 7%, and 6% (NMI) and 33%, 15% and 20% (MI), respectively (p < 0.01). Tim-3 expression also increased in PBMC NK and T cells and was also correlated with stage (NK: 19-32%, NMI/MI, CD4: 2-8%, NMI/MI, and CD8: 3-11%, NMI/MI, all p= < .05). TIGIT expression on NK and T cells did not increase with disease stage, but was significantly induced in PBMC and TIL in the presence of BCa, suggesting it may represent an early marker of immune dysfunction. (Figure 1)
Conclusions: We have identified TIM-3 and TIGIT as possible novel targets for patients with BCa. In the error of immunotherapy for patients with BCa these findings are important for clinical trial design.