Bum-Sup Jang1, Wonsik Han2, In Ah Kim3. 1. Department of Radiation Oncology, Seoul National University Bundang Hospital, Republic of Korea. 2. Department of Surgery, Seoul National University, College of Medicine, Republic of Korea. 3. Department of Radiation Oncology, Seoul National University Bundang Hospital, Republic of Korea; Department of Radiation Oncology, Seoul National University, College of Medicine, Republic of Korea. Electronic address: inah228@snu.ac.kr.
Abstract
INTRODUCTION: We analyzed transcriptional and mutational profile mainly focused on tumor mutation burden (TMB), immune checkpoint crosstalk, and radiosensitivity using scRNA-seq data derived from breast cancer and immune cells. MATERIALS AND METHODS: scRNA-seq transcriptome data were acquired from the GEO database (GSE75688). The radiosensitivity index (RSI) was used to evaluate radiosensitivity of each cell. CD274 mRNA expression was used to surrogate PD-L1 expression status. A computational approach was utilized for the immune and tumor cell group (N = 492) to identify potential interactions between tumor and immune cells with respect to immune checkpoint ligand-receptor gene pairs. Mutation data was profiled from raw scRNA-seq data of tumor cells acquired from both primary tumor and metastatic lymph node (N = 317). TMB and mutational signatures were compared between radiosensitive (RS) and radioresistant (RR) tumor cells. RESULTS: Most RR cells were a basal subtype and showed the higher rate of PD-L1 positivity. The patients with TNBC or HER2 subtype showed increased number of immune checkpoint ligand-receptor interactions between tumor and immune cells. PD-L1 ligand-receptor interactions between tumor cells and T cells were differentially increased in patients with the HER2 subtype compared to patients with the luminal subtype. Meanwhile, CTLA-4 ligand-receptor interactions were increased in patients with the TNBC subtype. TMB was significantly higher in RR cells than RS cells. Mutational signatures including microsatellite instability (MSI) and NRF2 pathway were altered in RR cells. CONCLUSIONS: RR cells exhibited a basal subtype, high PD-L1 expression, and high TMB with mutational signature found in tumors having MSI. Differential crosstalk between tumor and immune cells was associated with the patient subtype of breast cancer. These findings could be useful to identify potential biomarker(s) and optimal combination strategies of immune checkpoint blockades and radiation therapy in the management of breast cancer.
INTRODUCTION: We analyzed transcriptional and mutational profile mainly focused on tumor mutation burden (TMB), immune checkpoint crosstalk, and radiosensitivity using scRNA-seq data derived from breast cancer and immune cells. MATERIALS AND METHODS: scRNA-seq transcriptome data were acquired from the GEO database (GSE75688). The radiosensitivity index (RSI) was used to evaluate radiosensitivity of each cell. CD274 mRNA expression was used to surrogate PD-L1 expression status. A computational approach was utilized for the immune and tumor cell group (N = 492) to identify potential interactions between tumor and immune cells with respect to immune checkpoint ligand-receptor gene pairs. Mutation data was profiled from raw scRNA-seq data of tumor cells acquired from both primary tumor and metastatic lymph node (N = 317). TMB and mutational signatures were compared between radiosensitive (RS) and radioresistant (RR) tumor cells. RESULTS: Most RR cells were a basal subtype and showed the higher rate of PD-L1 positivity. The patients with TNBC or HER2 subtype showed increased number of immune checkpoint ligand-receptor interactions between tumor and immune cells. PD-L1 ligand-receptor interactions between tumor cells and T cells were differentially increased in patients with the HER2 subtype compared to patients with the luminal subtype. Meanwhile, CTLA-4 ligand-receptor interactions were increased in patients with the TNBC subtype. TMB was significantly higher in RR cells than RS cells. Mutational signatures including microsatellite instability (MSI) and NRF2 pathway were altered in RR cells. CONCLUSIONS: RR cells exhibited a basal subtype, high PD-L1 expression, and high TMB with mutational signature found in tumors having MSI. Differential crosstalk between tumor and immune cells was associated with the patient subtype of breast cancer. These findings could be useful to identify potential biomarker(s) and optimal combination strategies of immune checkpoint blockades and radiation therapy in the management of breast cancer.
Authors: G Daniel Grass; Juan C L Alfonso; Eric Welsh; Kamran A Ahmed; Jamie K Teer; Shari Pilon-Thomas; Louis B Harrison; John L Cleveland; James J Mulé; Steven A Eschrich; Heiko Enderling; Javier F Torres-Roca Journal: Int J Radiat Oncol Biol Phys Date: 2022-03-12 Impact factor: 8.013