Abstract B09: Heterogeneous fates of metastatic lesions linked to immune escape in an ovarian cancer patient
Authors: Jiménez-Sánchez Alejandro , Veeraraghavan Harini , Li Yanyun , Vargas Hebert Alberto , Gill Michael B. , Park Kay J. , Zivanovic Oliver , Konner Jason , Ricca Jacob , Zamarin Dmitriy , Aghajanian Carol , Wolchok Jedd D. , Merghoub Taha , Sala Evis , Snyder Alexandra , Miller Martin L. 
Published: March 2017

Abstract
The effect of chemotherapy on tumor heterogeneity and activation of the immune system in cancer is poorly understood. We present an unusual case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited spontaneous regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. The primary tumor was resected before chemotherapy treatment started. After 5 years of chemotherapy without response, treatment was stopped, the patient transitioned to best supportive care and was followed clinically with regular CA125 biomarker evaluation. During the course of 2 years of clinical follow up, CA125 decreased and computerized tomography (CT) scans revealed one regressing (right upper quadrant), one stable (liver), and two progressing (spleen and vaginal cuff) metastases. Due to abdominal discomfort, metastases were simultaneously resected. We performed: a) CT scan-based radiomics to anlayze tumor heterogeneity, b) exome sequencing to identify somatic mutations, predict neoepitopes, and estimate neoepitope depletion, and c) immunofluorescence staining to analyze immune cell infiltration on the primary and four metastatic tumors. We found that chemotherapy increases tumor heterogeneity, and metastases that developed after multi-line chemotherapy have a higher somatic mutation rate, more neoepitopes, and mutations in immune recognition molecules compared to metastases that appeared earlier. The right upper quadrant regressing and the liver stable metastases were infiltrated by CD4+ and CD8+ T cells. The vaginal cuff progressing metastasis was characterized by immune cell exclusion, while the spleen progressing metastasis was infiltrated only by CD8+ T cells. Finally, we detected neoepitope depletion only in the right upper quadrant regressing metastasis, potentially indicating an active immunoediting process. These findings indicate that multiple distinct tumor immune microenvironments can co-exist within a single individual, evidencing potential clinical challenges for the appropriate application of immunotherapy and chemotherapy combinations to overcome tumor heterogeneity at the genetic and tumor-microenvironment levels.
Citation Format: Alejandro Jiménez-Sánchez, Harini Veeraraghavan, Yanyun Li, Hebert Alberto Vargas, Michael B. Gill, Kay J. Park, Oliver Zivanovic, Jason Konner, Jacob Ricca, Dmitriy Zamarin, Carol Aghajanian, Jedd D. Wolchok, Taha Merghoub, Evis Sala, Alexandra Snyder, Martin L. Miller. Heterogeneous fates of metastatic lesions linked to immune escape in an ovarian cancer patient. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B09.