The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

Zhang, A. W.; McPherson, A.; Milne, K.; Kroeger, D. R.; Hamilton, P. T.; Miranda, A.; Funnell, T.; Laan, S.; Cochrane, D. R.; Lim, J. L. P.; Yang, W.; Roth, A.; Smith, M. A.; de Souza, C.; Ho, J.; Tse, K.; Zeng, T.; Shlafman, I.; Mayo, M. R.; Moore, R.; Failmezger, H.; Heindl, A.; Wang, Y. K.; Bashashati, A.; Brown, S. D.; Lai, D.; Wan, A. N. C.; Nielsen, C. B.; Bouchard-Cote, A.; Yuan, Y.; Wasserman, W. W.; Gilks, C. B.; Karnezis, A. N.; Aparicio, S.; McAlpine, J. N.; Huntsman, D. G.; Holt, R. A.; Nelson, B. H.; Shah, S. P.

doi:10.1101/198101

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bioRxiv · 10.1101/198101

The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

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Abstract

High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumor-infiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

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Zhang, A. W., McPherson, A., Milne, K., Kroeger, D. R., Hamilton, P. T., Miranda, A., Funnell, T., Laan, S., Cochrane, D. R., Lim, J. L. P., Yang, W., Roth, A., Smith, M. A., de Souza, C., Ho, J., Tse, K., Zeng, T., Shlafman, I., Mayo, M. R., Moore, R., Failmezger, H., Heindl, A., Wang, Y. K., Bashashati, A., Brown, S. D., Lai, D., Wan, A. N. C., Nielsen, C. B., Bouchard-Cote, A., Yuan, Y., Wasserman, W. W., Gilks, C. B., Karnezis, A. N., Aparicio, S., McAlpine, J. N., Huntsman, D. G., Holt, R. A., Nelson, B. H., Shah, S. P.. 2017-10-04. The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer. https://doi.org/10.1101/198101

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