Julie Schwarz, MD, PhD, presented her research in Paphos, Cyprus on November 1, 2024.
Her abstract:
The combination of radiation therapy (RT) and immune checkpoint blockade (ICB) increases anti-tumor immunity; however, not all patients and tumors respond to this combination. RT has well known immune suppressive effects including stimulating the expression of chemokines and cytokines that promote the migration of immune suppressive cell subsets into the tumor microenvironment (TME). Understanding RT-induced immune cell subset migration may explain why some tumors do not respond favorably to this combination. The Washington University METEOR center was established to collect and analyze longitudinally collected human tumor biopsies from patients with cervix and pancreas cancer treated with standard of care chemoradiation (SOC CRT). Here we report preliminary findings from our cervical cancer study using 2 approaches (bulk and single cell RNASeq). Deconvolution methods including Xcell and CIBERSORT were applied to bulk RNASeq data from N=17 pretreatment cervix tumor biopsies. The results demonstrated significant variability in the immune TME amongst pretreatment cervical tumors, with the largest differences observed for neutrophils and CD8 positive T cells. Treatment with SOC CRT was associated with significant increases in monocytes and neutrophils in the cervix TME and significant decreases in CD4 and CD8 positive T cells. Using single cell RNASeq data from N=9 pretreatment tumor biopsies, we performed custom subclustering to further refine immune cell subpopulations in the cervix TME. In the myeloid compartment, we identified monocytes, two unique populations of macrophages, 3 populations of neutrophils and 2 populations of dendritic cells. Comparison of the single cell RNASeq data obtained from pretreatment to Week 1 and Week 2 of SOC CRT revealed dynamic treatment-associated changes in each of these compartments. In the lymphoid compartment, 1 week of treatment with SOC CRT is associated with decreases across the board in all T cell subtypes, which begin to rebound at 2 weeks of SOC CRT. In the myeloid compartment, 1 week of treatment with SOC CRT is associated with significant decreases in dendritic cells (DCs) with simultaneous increases in macrophages and neutrophils. After 2 weeks of SOC CRT, persistent increases in monocytes, macrophages, and neutrophils are noted. Differential analysis of gene expression data demonstrated that SOC CRT is associated with induction of p53, chemokine and interleukin signaling pathways in immune cell subpopulations which may contribute to an overall immune suppressive phenotype. These results suggest that SOC CRT is associated with induction of p53, chemokine and cytokine signalling pathways that promote decreases in T cell number and infiltration by myeloid derived cells in the cervix TME. Work is ongoing in preclinical models to determine whether targeting treatment induced myeloid cell subpopulations within cervix tumors may improve outcomes after RT.