Potential immunotherapy targets in recurrent cervical cancer.

OBJECTIVE: Our objective was to characterize the intra and peritumoral immune profile in recurrent cervical cancers to identify rational immunotherapy targets.

METHODS: Archival pelvic exenteration specimens were examined using a validated multiplex immuno-fluorescent panel of antibodies against cluster of differentiation 8 (CD8), cluster of differentiation 68 (CD68), forkhead box P3 (FoxP3), programmed cell death protein 1 (PD1), and programmed death-ligand 1 (PD-L1, N=28). Clinical data were abstracted from the electronic medical record.

RESULTS: Cytotoxic T cells, macrophages, and regulatory T cells were found in higher densities in peritumoral stroma (CD8+ density 497.7 vs 83.5, p<0.0001, CD68+ density 345.0 vs 196.7, p=0.04, FoxP3+ density 214.5 vs 35.6, p<0.0001). Antigen experienced T cells (PD1+) were higher in peritumoral compared to tumor tissue (median normalized fluorescence intensity 0.05 vs 0.0085, p<0.001). Although there was a higher median density of intratumoral cytotoxic T cells and macrophages compared to regulatory T cells (median density CD8+ 83.5 vs 35.6, p<0.05, median density 196.7 vs 35.6, p<0.05), the presence of macrophages correlated with the presence of regulatory T cells in tumors (r=0.58, p=0.001).

CONCLUSIONS: While cytotoxic T cells are present in tumor tissue to varying degrees, their density is lower than in peritumoral stroma, suggesting intratumoral exclusion or destruction of T cells. Higher densities of intratumoral macrophages compared to regulatory T cells suggest macrophages may be important contributors to the immunosuppressive tumor environment. Future directions for combination therapy include altering T cell trafficking and targeting tumor associated macrophages (TAMs) to enhance intratumoral activated T cell density and effect a more robust immune response.