Gina Mantia-Smaldone1, Lukas Ronner2, Anne Blair3, Victoria Gamerman3, Christopher Morse2, Sandra Orsulic4, Stephen Rubin5, Phyllis Gimotty3, Sarah Adams6. 1. Section of Gynecologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Electronic address: gina.mantia-smaldone@fccc.edu. 2. Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, 3rd Floor, PCAM, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. 3. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 501 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA. 4. Women's Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. 5. Section of Gynecologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. 6. Division of Gynecologic Oncology, University of New Mexico Cancer Center, 1201 Camino de Salud NE, 1 University of New Mexico, Albuquerque, NM 87106, USA.
Abstract
OBJECTIVE: Women with BRCA-associated ovarian cancer demonstrate excellent responses to Pegylated Liposomal Doxorubicin (PLD). PLD has also been shown to enhance T cell recognition of tumor cells. Here we characterize immunophenotypic changes associated with BRCA1 dysfunction in ovarian cancer cells, and evaluate the T cell contribution to the therapeutic efficacy of PLD in a BRCA1- ovarian cancer model to determine whether enhanced anti-tumor immunity contributes to the improved response to PLD in BRCA1- ovarian cancers. METHODS: The immunophenotype of BRCA1- and wild-type (WT) ovarian cancer cells and their response to PLD were compared in vitro using flow cytometry. T cell recruitment to BRCA1- tumors was evaluated with flow cytometry and immunohistochemistry. The contribution of T cell populations to the therapeutic effect of PLD in a BRCA1- model was evaluated using immunodepleting antibodies with PLD in vivo. RESULTS: The cytotoxic response to PLD was similar in BRCA1- and WT cells in vitro. BRCA1- inactivation resulted in higher expression of Fas and MHC-I at baseline and after PLD exposure. PLD prolonged the survival of BRCA1- tumor bearing mice and increased intratumoral T cell recruitment. CD4+ depletion combined with PLD significantly prolonged overall survival (p=0.0204) in BRCA1- tumor-bearing mice. CONCLUSION: Differences in the immunophenotype of BRCA1- and WT cells are amplified by PLD exposure. The enhanced immunomodulatory effects of PLD in BRCA1- tumors may be exploited therapeutically by eliminating suppressive CD4+ T cells. Our results support further study of combination therapy using PLD and immune agents, particularly in women with BRCA gene mutations.
OBJECTIVE:Women with BRCA-associated ovarian cancer demonstrate excellent responses to Pegylated Liposomal Doxorubicin (PLD). PLD has also been shown to enhance T cell recognition of tumor cells. Here we characterize immunophenotypic changes associated with BRCA1 dysfunction in ovarian cancer cells, and evaluate the T cell contribution to the therapeutic efficacy of PLD in a BRCA1- ovarian cancer model to determine whether enhanced anti-tumor immunity contributes to the improved response to PLD in BRCA1- ovarian cancers. METHODS: The immunophenotype of BRCA1- and wild-type (WT) ovarian cancer cells and their response to PLD were compared in vitro using flow cytometry. T cell recruitment to BRCA1- tumors was evaluated with flow cytometry and immunohistochemistry. The contribution of T cell populations to the therapeutic effect of PLD in a BRCA1- model was evaluated using immunodepleting antibodies with PLD in vivo. RESULTS: The cytotoxic response to PLD was similar in BRCA1- and WT cells in vitro. BRCA1- inactivation resulted in higher expression of Fas and MHC-I at baseline and after PLD exposure. PLD prolonged the survival of BRCA1- tumor bearing mice and increased intratumoral T cell recruitment. CD4+ depletion combined with PLD significantly prolonged overall survival (p=0.0204) in BRCA1- tumor-bearing mice. CONCLUSION: Differences in the immunophenotype of BRCA1- and WT cells are amplified by PLD exposure. The enhanced immunomodulatory effects of PLD in BRCA1- tumors may be exploited therapeutically by eliminating suppressive CD4+ T cells. Our results support further study of combination therapy using PLD and immune agents, particularly in women with BRCA gene mutations.
Authors: Tomoe Higuchi; Dallas B Flies; Nicole A Marjon; Gina Mantia-Smaldone; Lukas Ronner; Phyllis A Gimotty; Sarah F Adams Journal: Cancer Immunol Res Date: 2015-07-02 Impact factor: 11.151
Authors: Robert L Hollis; Alison M Meynert; Michael Churchman; Tzyvia Rye; Melanie Mackean; Fiona Nussey; Mark J Arends; Andrew H Sims; Colin A Semple; C Simon Herrington; Charlie Gourley Journal: BMC Cancer Date: 2018-01-03 Impact factor: 4.430
Authors: Annamaria Ferrero; Martina Borghese; Stefano Restaino; Andrea Puppo; Giuseppe Vizzielli; Nicoletta Biglia Journal: Int J Environ Res Public Health Date: 2022-04-02 Impact factor: 3.390