Distinct Tumor-Immune Microenvironments Occur at Different Tumor Sites

In patients with metastatic ovarian cancer, tumor heterogeneity can affect the response to immunotherapy; however, the effects of chemotherapy on tumor heterogeneity and on immune responses remain poorly understood. In a case study of a patient with high-grade serous ovarian cancer, Jiménez-Sánchez and colleagues performed immunogenomic analyses to examine several metastases that exhibited concomitant regression and progression after multiple lines of chemotherapy. The patient underwent surgical debulking followed by paclitaxel in combination with cisplatin then carboplatin. At disease recurrence, the patient was treated with multiple chemotherapy regimens over a period of 3 years. She transitioned to supportive care, and underwent another surgical debulking. Whole-exome sequencing of normal blood, the resected primary tumor, and 4 metastatic sites [liver, spleen, right upper quadrant (RUQ), and vaginal cuff] allowed phylogenetic analysis. The liver and vaginal cuff lesions were the most genetically heterogeneous, and several potential driver mutations were detected in all tumor sites. Although mutations were not detected in immune-related genes, immune-related pathways were overexpressed in regressing tumors. Consistent with these findings, immune cell infiltration differed between samples. The primary tumor displayed no T-cell or macrophage infiltration. The vaginal cuff lesion, which was growing at surgical resection, did not harbor tumor-infiltrating T cells. The splenic lesion, which was progressing at a slower rate, had infiltrating CD8⁺ cells. The regressing RUQ metastasis and stable liver metastases exhibited strong CD4⁺ and CD8⁺ T-cell infiltration, higher expression of HLA genes, and oligoclonal expansion of specific T-cell subsets. Further, peripheral blood CD8⁺ T-cell reactivity against predicted tumor neoantigens was observed nearly 3 years after the tumors were resected. The finding that each metastatic site is comprised of a distinct tumor-immune microenvironment in a patient with metastatic ovarian cancer suggests that immune microenvironment heterogeneity may pose a challenge to the success of immunotherapies in this setting.

Jiménez-Sánchez A, Memon D, Pourpe S, Veeraraghavan H, Li Y, Vargas HA, et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 2017;170:927–38.e20.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.