Abstract
Glucocorticoids are a class of steroid hormones essential to the modulation of a number of physiologic processes, including cellular metabolism, neural development and immune system function. Functions of glucocorticoids are mediated through the glucocorticoid receptor (GR). Synthetic glucocorticoids are front-line therapies in the clinic for leukemia and lymphoma due to their potent induction of lymphocyte death. Glucocorticoids are also prescribed as adjuvant therapies to chemotherapies to alleviate adverse effects including nausea, emesis and allergic reactions. In the current regimen of immune checkpoint blockade therapies against solid tumors, glucocorticoids are incorporated to manage symptoms related to acute immune hyperactivation. However, given that glucocorticoids preferentially cause lymphocyte death, their inclusion in immune checkpoint blockade regimens which capitalize on cytotoxic T-cell-mediated killing of tumor cells is controversial. The precise effects of systematic glucocorticoids use on tumor development, and particularly, on the tumor-immune microenvironment comprised tumor-infiltrating leukocytes (TILs) remains unknown. Conversely, methods to antagonize glucocorticoid signaling could potentially boost lymphocyte number and function and potentiate cytotoxic T-cell-mediated killing of tumor cells. Presently, the treatment of “immune cold” solid tumor types remains a challenge for immunotherapy due low level of TILs and presence of immunosuppressive cells (including regulatory T-cells and myeloid-derived suppressor cells) in the tumor microenvironment. Pharmacologic modulation of GR presents a unique opportunity to regulate immune cell homeostasis and function with the goal of promoting a favorable tumor immune microenvironment to augment the effectiveness of cancer immunotherapies in solid tumors. Our research seeks to understand the impact of glucocorticoid modulation in the context of immune checkpoint blockade therapies in preclinical models, and to provide a rationale for selective pharmacologic modulation of GR to promote a favorable tumor immune microenvironment and increased efficacy of immunotherapies in solid tumors. We investigated GR activation and inhibition on the immune tumor microenvironment in murine syngeneic melanoma (B16), breast cancer (4T1) and colorectal cancer (CT26) models. Mice bearing allograft tumors were randomized into groups receiving synthetic glucocorticoids or GR inhibitors in combination with anti-PD-1 and anti-CTLA4 therapies. Following treatment, tumors were assessed for composition of intratumoral leukocyte infiltration by flow cytometry phenotyping. In the mouse breast cancer model (4T1), we found evidence supporting substantial lymphodepletion by dexamethasone (a synthetic glucocorticoid compound). Treatment with PD-1 and CTLA-4 blocking monoclonal antibodies increased lymphocyte infiltration into the tumor. Interestingly, immune checkpoint blockade therapies significantly raised the number of more CD4+ T helper cells than CD8+ cytotoxic T-cells in the tumor. Our future plan includes investigation of the effects of GR inhibition on TILs in murine solid tumor models, and utilization of RNA-sequencing on TILs for identification of genes and molecular pathways that provide opportunities to boost TIL function within the tumor. In summary, our work can provide insight into the fundamental molecular mechanisms by which the glucocorticoid receptor modulates the tumor immune microenvironment and provide novel avenues for enhancing cancer immunotherapies in solid tumors.
Citation Format: Qin Tang, Myles A. Brown. Modulating glucocorticoid receptor-mediated signaling for enhancement of cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A218.