title: Potential immunotherapy targets in recurrent cervical cancer.
abstract: Our objective was to characterize the intra and peritumoral immune profile in recurrent cervical cancers to identify rational immunotherapy targets.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Health System, PO Box 800712, Charlottesville, VA, United States. Electronic address: kel7j@virginia.edu.
authors.forename: Kari L
authors.initials: KL
authors.lastname: Ring
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, United States. Electronic address: ayemeyanova@mdanderson.org.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Yemelyanova
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1362, Houston, TX, United States. Electronic address: psoliman@mdanderson.org.
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Soliman
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1362, Houston, TX, United States. Electronic address: mfrumovitz@mdanderson.org.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Frumovitz
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1362, Houston, TX, United States. Electronic address: aajazaeri@mdanderson.org.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Jazaeri
mesh_terms: D060890:B7-H1 Antigen / Q000276:immunology; D005260:Female; D005557:Formaldehyde; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D058990:Molecular Targeted Therapy; D016612:Paraffin Embedding; D012189:Retrospective Studies; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016707:Tissue Fixation; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000628:therapy*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D005557:Formaldehyde
keywords: Cervical cancer; Immune checkpoint inhibitors; Immunotherapy