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.