Kari L Ring1, Anna V Yemelyanova2, Pamela T Soliman3, Michael M Frumovitz4, Amir A Jazaeri5. 1. 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. 2. Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, United States. Electronic address: ayemeyanova@mdanderson.org. 3. 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. 4. 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. 5. 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.
Abstract
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.
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.
Authors: John M Floberg; Jin Zhang; Naoshad Muhammad; Todd A DeWees; Matthew Inkman; Kevin Chen; Alexander J Lin; Ramachandran Rashmi; Kay Jayachandran; Brian T Edelson; Barry A Siegel; Farrokh Dehdashti; Perry W Grigsby; Stephanie Markovina; Julie K Schwarz Journal: Clin Cancer Res Date: 2021-04-05 Impact factor: 12.531
Authors: Dimakatso Alice Senthebane; Arielle Rowe; Nicholas Ekow Thomford; Hendrina Shipanga; Daniella Munro; Mohammad A M Al Mazeedi; Hashim A M Almazyadi; Karlien Kallmeyer; Collet Dandara; Michael S Pepper; M Iqbal Parker; Kevin Dzobo Journal: Int J Mol Sci Date: 2017-07-21 Impact factor: 5.923
Authors: Jason Roszik; Kari L Ring; Khalida M Wani; Alexander J Lazar; Anna V Yemelyanova; Pamela T Soliman; Michael Frumovitz; Amir A Jazaeri Journal: Front Immunol Date: 2018-09-19 Impact factor: 7.561