Microenvironment Heterogeneity May Contribute to Lack of Immunotherapy Success in High-Grade Serous Ovarian Cancer

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INTER- AND INTRAPATIENT heterogeneity of the tumor microenvironment may explain the limited success of checkpoint blockade thus far observed in patients with advanced high-grade serous ovarian cancer, according to Paulina Cybulska, MD, MSc, of Memorial Sloan Kettering Cancer Center in New York. 

Paulina Cybulska, MD, MSc

Paulina Cybulska, MD, MSc

Aggressive surgical debulking in combination with platinum-based chemotherapy is the mainstay of treatment for this population. These interventions allow the majority of patients to achieve full clinical remission, but almost all will have a recurrence and develop platinum-resistant disease during subsequent treatment. Although immunotherapies have emerged as an important therapeutic modality for a broad range of cancers, their effect on ovarian cancer has been modest. A key factor contributing to this therapeutic failure and drug resistance is believed to be intra- and intertumoral heterogeneity. 

Dr. Cybulska and her colleagues at Memorial Sloan Kettering conducted an internal analysis of patients with recurrent primary serous ovarian cancer treated with checkpoint blockade; they found that 66% of patients experienced a “mixed response.” That is, within the same patient, some tumors shrunk, some were stable, and others grew. “This incongruity between response rate and disease control rate is quite characteristic of immunotherapies,” she said at the 2018 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.1 

Research has shown that patients with metastatic ovarian cancer exhibit heterogeneity at the genomic level even prior to the initiation of treatment. The researchers sought to find out whether this genomic heterogeneity is mirrored by similar heterogeneity in the tumor microenvironment and whether multiple, distinct tumor microenvironments exist within the same patient. Further, they wanted to examine which cells contribute to the interpatient heterogeneity. 

Complete, Distinct Microenvironments 

Tumor samples were collected prospectively from eight patients undergoing primary debulking surgery for advanced-stage disease, with a median of five sites sampled per patient. The investigators performed immunofluorescent staining and quantification of CD4-positive, CD8-positive, and regulatory T cells in at least 10 tumor regions in each sample. They found that patients had marked variability in infiltrating T cells, ranging from barely detectable to highly abundant. They also found clear differences in T-cell staining between various tumor deposits from the same patient. 

“This multiregional analysis shows that high-grade serous cancers are characterized by the presence of heterogeneous tumor immune microenvironments across patients, anatomic sites, and even within the same individual and tumor deposit.”
— Paulina Cybulska, MD, MSc

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“This multiregional analysis shows that high-grade serous cancers are characterized by the presence of heterogeneous tumor immune microenvironments across patients, anatomic sites, and even within the same individual and tumor deposit,” she said. 

From the same eight patients, Dr. Cybulska and her colleagues analyzed the transcriptome of these primary metastatic tumors to look at how samples compared to one another and to the population. They found that, overall, the immune scores of the cohort fell within the expected range based on single-site samples from The Cancer Genome Atlas. They then compared scores across patients and found that the immune score varied substantially. 

“Interestingly, some patients showed a level of immune score variation between their own tumor samples comparable to the variation observed across patients at the population level, indicating that even within a single individual, complete distinct immune microenvironments can coexist at the time of diagnosis,” Dr. Cybulska said. 

Overall transcriptome analysis showed largely patient-specific, rather than site-specific, transcriptome-driven structure: Although each patient displayed intersite heterogeneity in gene expression, in most cases, all sites within a patient were more similar to each other than to any site from another patient, she reported. 

Next they performed single-sample gene set enrichment analysis and found that cancer-, immune-, and stroma-associated gene signatures could explain most of the gene set expression variation. Finally, they investigated which hallmark gene sets were differentially expressed between pure and impure tumors. As expected, immunostromal signatures were more highly enriched in infiltrated tumors. 

“These data demonstrate that even before exposure to systemic therapy, a subset of high-grade serous ovarian cancers show substantial intra- and intersite heterogeneity,” said Dr. Cybulska. “Second, they underscore the importance of the activation of certain pathways—including MYC and WNT—to immune evasion.” 

If generalizable, these findings pose challenges to the application of checkpoint blockade therapies in high-grade serous ovarian cancer, she said, suggesting that additional immunomodulation may be required to ensure that all sites of disease are effectively targeted by the immune system. ■

DISCLOSURE: Dr. Cybulska reported no conflicts of interest. 


1. Cybulska P, et al: 2018 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract 50. Presented March 27, 2018.

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