Webinar
Adjuvant COX Inhibition Augments Cytolytic T Cell Infiltration in Irradiated Triple Negative Breast Tumors
On-demand
Immune therapy has emerged as the new frontier of cancer treatment. Therapeutic radiation is a known inducer of an immune response that can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2), which is highly expressed in triple negative breast tumors.
A clinical cohort of triple negative breast cancer (TNBC) tumors revealed that elevated COX2 tumor expression predicted poor radiation therapeutic efficacy. Using the aggressive murine 4T1 TNBC model, we show that treatment with ionizing radiation and adjuvant NSAID (indomethacin) therapy to inhibit COX2 provides a powerful combination to reduce both primary tumor growth and lung metastasis through immune modulation.
Using whole tumor RNAseq and multiplex fluorescence imaging, this study reveals spatial immunological changes in the treated primary tumor. Indomethacin alone increased the infiltration of lymphoid populations into the primary tumor. Importantly, the combined treatment improved lymphoid infiltration into the tumor epithelium, augmented cGAS/STING1 and type I IFN gene expression andaltered key immune checkpoints including PD1, IDO, and CTLA4. Markedly increased B cell and T cell populations with increased CD8 + T cell activation and reduced T cell exhaustion were observed. Thus, adjuvant NSAID treatment combined with radiation therapy shifts “immune desert phenotypes” toward anti-tumor immune mediators favoring M1/Th1 signatures in the immunologically challenging 4T1 tumor model.
Importantly, radiation/indomethacin combination improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared to mice treated with single agent radiation. These results show that clinically available NSAID’s augment radiation therapeutic efficacy through improved antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Lisa A. Ridnour Ph.D
Dr. Ridnour received her PhD from the late Dr. Larry Oberley where her work demonstrated an imbalance in peroxide generating versus peroxide metabolizing enzymes in the tumor suppressive effects of MnSOD. She completed her post-doctoral training at Washington University in the laboratory of Dr. Douglas Spitz, where she identified thiol-dependent mechanisms associated with NO-induced resistance to peroxide stress. Dr. Ridnour joined the research group of Dr. David Wink (NCI) in 2003 where her research interests include NO regulation of extracellular matrix during cancer progression. In collaboration with Dr. David Roberts (NCI), she discovered a novel biphasic crosstalk relationship between NO and the angiogenesis inhibitor thrombospondin-1 (TSP-1). Her collaborations with Dr. Stefan Ambs (NCI), showed correlations between NOS2 and both TIMP-1 and MMP-9 in breast cancer survival where tyrosine nitration at two key residues critical for TIMP-1 inhibition of MMP-9 activity was identified. This nitration event occurred at NO concentrations that increase MMP-9 secretion and activity as well as TIMP-1 binding to its receptor CD63, which promotes tumor cell survival through CD63/PIK3/AKT/BAD signaling. Her collaboration with Dr. Carol Colton at Duke University demonstrated a protective role for NO regulation of MMP-9/TIMP-1 balance and increased plaque clearance in Alzheimer's disease. These studies have demonstrated a regulatory role of NO in matrix reorganization as it occurs in inflammatory diseases. Her current studies involve examination of NOS2/COX2 regulation of the tumor immune microenvironment where she demonstrated that NOS inhibition improved radiation therapeutic efficacy by limiting IL-10-mediated immunosuppression. This work has in part led to the development of spatial imaging platforms for more detailed spatial analyses of how tumor NOS2/COX2 expression direct the tumor immune microenvironment in aggressive cancers. These studies have revealed that COX inhibition using clinically available NSAIDs improves radiation therapeutic efficacy, which involves in part augmented M1/Th1 antitumor immune response.