Nicholas G Battaglia1, Taylor P Uccello1, Angie Hughson2, Jesse Garrett-Larsen2, Johnathan J Caldon1, Haoming Qiu3, Scott A Gerber2, Edith M Lord4. 1. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York. 2. Department of Surgery, University of Rochester Medical Center, Rochester, New York. 3. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York. 4. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York. Electronic address: edith_lord@urmc.rochester.edu.
Abstract
PURPOSE: Dexamethasone is commonly given during radiation therapy (RT) to manage toxicities. Our study examines if dexamethasone coadministration with RT inhibits the RT-induced antitumor T cell response in mouse. METHODS AND MATERIALS: Intramuscularly implanted MC38 tumors were irradiated with 15 Gy after establishing for 7 days. Tumor bearing mice were administered dexamethasone using multiple schedules and doses. Peripheral lymphocyte reduction was monitored by complete blood count and intratumoral and tumor draining lymph node (tdLN) populations by flow cytometry. Effector phenotype and function of ex vivo stimulated tumor-infiltrating lymphocytes (TILs) and naïve splenocytes as well as in vivo TILs with or without dexamethasone were monitored by flow cytometry and ELISA. RESULTS: Long course high dose, short course high dose, and short course human equivalent dose dexamethasone reduced peripheral lymphocytes yet did not inhibit survival after irradiation. Short course high dose administration decreased TIL and tdLN lymphocyte activation as well as tdLN mass but did not affect TIL frequencies or change tdLN cell population composition. Dexamethasone inhibited effector function of ex vivo stimulated naïve splenocytes and TILs, but magnitude of IFN-γ secretion was consistently higher in TILs regardless of dexamethasone dose. In vivo analysis of TILs after irradiation and HE dexamethasone treatment showed that TILs had a similar effector phenotype compared with vehicle controls. CONCLUSIONS: Dexamethasone reduces blood and tdLN lymphocytes. Dexamethasone also suppresses TIL activation/effector function yet does not affect survival in irradiated MC38 tumor bearing mice, which depend on RT-induced immune responses for therapy efficacy. Additional study in human subjects is warranted.
PURPOSE: Dexamethasone is commonly given during radiation therapy (RT) to manage toxicities. Our study examines if dexamethasone coadministration with RT inhibits the RT-induced antitumor T cell response in mouse. METHODS AND MATERIALS: Intramuscularly implanted MC38 tumors were irradiated with 15 Gy after establishing for 7 days. Tumor bearing mice were administered dexamethasone using multiple schedules and doses. Peripheral lymphocyte reduction was monitored by complete blood count and intratumoral and tumor draining lymph node (tdLN) populations by flow cytometry. Effector phenotype and function of ex vivo stimulated tumor-infiltrating lymphocytes (TILs) and naïve splenocytes as well as in vivo TILs with or without dexamethasone were monitored by flow cytometry and ELISA. RESULTS: Long course high dose, short course high dose, and short course human equivalent dose dexamethasone reduced peripheral lymphocytes yet did not inhibit survival after irradiation. Short course high dose administration decreased TIL and tdLN lymphocyte activation as well as tdLN mass but did not affect TIL frequencies or change tdLN cell population composition. Dexamethasone inhibited effector function of ex vivo stimulated naïve splenocytes and TILs, but magnitude of IFN-γ secretion was consistently higher in TILs regardless of dexamethasone dose. In vivo analysis of TILs after irradiation and HE dexamethasone treatment showed that TILs had a similar effector phenotype compared with vehicle controls. CONCLUSIONS: Dexamethasone reduces blood and tdLN lymphocytes. Dexamethasone also suppresses TIL activation/effector function yet does not affect survival in irradiated MC38 tumor bearing mice, which depend on RT-induced immune responses for therapy efficacy. Additional study in human subjects is warranted.
Authors: Derin B Keskin; Annabelle J Anandappa; Jing Sun; Itay Tirosh; Nathan D Mathewson; Shuqiang Li; Giacomo Oliveira; Anita Giobbie-Hurder; Kristen Felt; Evisa Gjini; Sachet A Shukla; Zhuting Hu; Letitia Li; Phuong M Le; Rosa L Allesøe; Alyssa R Richman; Monika S Kowalczyk; Sara Abdelrahman; Jack E Geduldig; Sarah Charbonneau; Kristine Pelton; J Bryan Iorgulescu; Liudmila Elagina; Wandi Zhang; Oriol Olive; Christine McCluskey; Lars R Olsen; Jonathan Stevens; William J Lane; Andres M Salazar; Heather Daley; Patrick Y Wen; E Antonio Chiocca; Maegan Harden; Niall J Lennon; Stacey Gabriel; Gad Getz; Eric S Lander; Aviv Regev; Jerome Ritz; Donna Neuberg; Scott J Rodig; Keith L Ligon; Mario L Suvà; Kai W Wucherpfennig; Nir Hacohen; Edward F Fritsch; Kenneth J Livak; Patrick A Ott; Catherine J Wu; David A Reardon Journal: Nature Date: 2018-12-19 Impact factor: 49.962
Authors: Kathryn C Arbour; Laura Mezquita; Niamh Long; Hira Rizvi; Edouard Auclin; Andy Ni; Gala Martínez-Bernal; Roberto Ferrara; W Victoria Lai; Lizza E L Hendriks; Joshua K Sabari; Caroline Caramella; Andrew J Plodkowski; Darragh Halpenny; Jamie E Chaft; David Planchard; Gregory J Riely; Benjamin Besse; Matthew D Hellmann Journal: J Clin Oncol Date: 2018-08-20 Impact factor: 44.544
Authors: Scott A Gerber; Abigail L Sedlacek; Kyle R Cron; Shawn P Murphy; John G Frelinger; Edith M Lord Journal: Am J Pathol Date: 2013-04-12 Impact factor: 4.307
Authors: Kenneth L Pitter; Ilaria Tamagno; Kristina Alikhanyan; Amira Hosni-Ahmed; Siobhan S Pattwell; Shannon Donnola; Charles Dai; Tatsuya Ozawa; Maria Chang; Timothy A Chan; Kathryn Beal; Andrew J Bishop; Christopher A Barker; Terreia S Jones; Bettina Hentschel; Thierry Gorlia; Uwe Schlegel; Roger Stupp; Michael Weller; Eric C Holland; Dolores Hambardzumyan Journal: Brain Date: 2016-03-28 Impact factor: 13.501
Authors: Kelli A Connolly; Brian A Belt; Nathania M Figueroa; Aditi Murthy; Ankit Patel; Minsoo Kim; Edith M Lord; David C Linehan; Scott A Gerber Journal: Oncotarget Date: 2016-12-27
Authors: Amber J Giles; Marsha-Kay N D Hutchinson; Heather M Sonnemann; Jinkyu Jung; Peter E Fecci; Nivedita M Ratnam; Wei Zhang; Hua Song; Rolanda Bailey; Dionne Davis; Caitlin M Reid; Deric M Park; Mark R Gilbert Journal: J Immunother Cancer Date: 2018-06-11 Impact factor: 13.751