Tumor evolution selectively inactivates the core microRNA machinery for immune evasion

Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system.

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Cancer immunotherapies such as immune checkpoint blockade (ICB) unleash T cell cytotoxicity against cancer cells and have significantly improved the perspective of cancer patients. However, a majority of cancer patients fail to benefit durably from immunotherapies, mostly due to the cancer-intrinsic accumulation of somatic mutations driving primary and acquired resistance to the treatment1-3. Cancer cells accumulate a myriad of genetic and epigenetic alterations to enable escaping from host immune elimination4. It is a great challenge to single out those alterations driving immune evasion and to unravel how they empower cancer cells against the hostile immunity5.

 On December 1, 2021, we published an article entitled  "Tumor evolution selectively inactivates the core microRNA machinery for immune evasion" in Nature Communication. We applied progressive immune pressure to cancer cell line-derived xenograft tumor development to identify T cell-defying spontaneous or rare mutations during clonal evolution. By combining massive parallel tumor sequencing and in vivo CRISPR library screen, we found that inactivation of the microRNA (miRNA) biogenesis and targeting machinery, particularly the AGO2 phosphorylation cycle, protects cancer cells from T cell-mediated killing. Mechanistically, the core miRNA machinery is required for interferon-γ signaling, chemokine expression and antigen presentation mainly by enabling miRNA-mediated SOCS1 silencing. The clinical relevance of the discovery is exemplified by the finding that expression of each miRNA machinery component correlates negatively with SOCS1 levels and positively with intratumoral T cell abundance across a large number of human cancer types. 

The core miRNA processing machinery is frequently mutated or downregulated to cause global miRNA depletion in cancer. Here we demonstrate for the first time that immune evasion as a major mechanism underlying the oncogenic function of mal-functional miRNA machinery, providing broad implications for patient stratification for the responsiveness of immunotherapy. Additionally, we propose a strategy to untangle cancer genetic heterogeneity for discovery of unanticipated pathways in driving cancer survival from immune selection or therapy.

 


Model of miRNA machinery in regulation of cancer-intrinsic evasion from T cell attack.

Dr. Tian-Yu Song, a postdoctoral of Cang Lab, is the first author of this article. Min Long from Zhejiang University and Dr. Hai-Xin Zhao from Oncology and Immunology department of WuxiApptec are the co-first authors. Dr. Yong Cang, a professor from the School of Life Science and Technology of ShanghaiTech University, corresponds this article. Miaowen Zou, an undergraduate student, and Hongjie Fan and Yang Liu, master graduate students at ShanghaiTech, have made important contributions to this research under the guidance of Dr. Song. This research was also supported by Prof. H. P. Wang at ShanghaiTech for immunological suggestions; Prof. L.Y. Zhang at SHTU, X. X. Xie, and Q. Qian at WuXi for bioinformatic suggestions; Prof. B. Sun at SIBCB for discussions and the gift of OT-I mice; Prof. L.F. Lu at UCSD for assistance with luciferase reporter assay; Y. N. Li at ZJU for coloring the mouse in the schematic. T.Y. Song was supported by Shanghai Post-doctoral Excellence Program from Shanghai Municipal Human Resources and Social Security Bureau. This research was funded by 2019M651613 and 2020T130669 (T.Y. Song) from China Postdoctoral Science Foundation; 82003803 (T.Y. Song), 92053118 and 31970671 (Y. Cang) from National Natural Science Foundation of China; and 18JC1413900 (Y. Cang) from Shanghai Science and Technology Committee.

  

Reference 

1                Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 168, 707-723, doi:10.1016/j.cell.2017.01.017 (2017).

2                Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nature Reviews Cancer 19, 133-150, doi:10.1038/s41568-019-0116-x (2019).

3                Hegde, P. S. & Chen, D. S. Top 10 Challenges in Cancer Immunotherapy. Immunity 52, 17-35, doi:10.1016/j.immuni.2019.12.011 (2020).

4                Maire, C. L. et al. Glioma escape signature and clonal development under immune pressure. J Clin Invest, doi:10.1172/JCI138760 (2020).

5                Galon, J. & Bruni, D. Tumor Immunology and Tumor Evolution: Intertwined Histories. Immunity 52, 55-81, doi:10.1016/j.immuni.2019.12.018 (2020).

 

Tian-Yu Song

Ph.D., ShanghaiTech University

I have always been intrigued by how cancer escape clearance by host immunity or therapeutic agents. To answer this question, I designed and performed multiple CRISPR library screenings in engrafted tumors with different immune selection, cancer-immune cell co-cultures and drug-induced cytotoxicity systems. I identified the core microRNA machinery (Nature Communications, 2021) or the epigenetic regulator KDM6A-KMT2D complex (In Submission) as key cancer-intrinsic modulators of response to T cell-mediated immunity and immunotherapy from tumor evolution. Also, I uncovered the regulation of CRBN level and CRL4CRBN E3 ubiquitin ligase activity by COP9 signalosome (Leukemia, 2019) and another E3 ligase SCFFbxo7 (Plos Genetics, 2018), indicating a critical role of such regulation for immunomodulatory drugs and their derivates (PROTAC and molecular glue degraders) to induce oncoprotein degradation and cytotoxicity. As a recognition of my research achievements, I have been awarded Super Post-doctoral Fellowship of Shanghai City, General and Special Programs of Postdoctoral Science Foundation of China, and National Natural Science Foundation of China for Young Scholar.