Meng Xiao He, Michael S. Cuoco, Jett Crowdis, Alice Bosma-Moody, Zhenwei Zhang, Kevin Bi, Abhay Kanodia, Mei-Ju Su, Sheng-Yu Ku, Maria Mica Garcia, Amalia R. Sweet, Christopher Rodman, Laura DelloStritto, Rebecca Silver, John Steinharter, Parin Shah, Benjamin Izar, Nathan C. Walk, Kelly P. Burke, Ziad Bakouny, Alok K. Tewari, David Liu, Sabrina Y. Camp, Natalie I. Vokes, Keyan Salari, Jihye Park, Sébastien Vigneau, Lawrence Fong, Joshua W. Russo, Xin Yuan, Steven P. Balk, Himisha Beltran, Orit Rozenblatt-Rosen, Aviv Regev, Asaf Rotem, Mary-Ellen Taplin, and Eliezer M. Van Allen. 3/4/2021. “Transcriptional mediators of treatment resistance in lethal prostate cancer.” Nature Medicine, Pp. 1–8. Publisher's VersionAbstract
Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies. Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2. Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.
Ziad Bakouny, David A. Braun, Sachet A. Shukla, Wenting Pan, Xin Gao, Yue Hou, Abdallah Flaifel, Stephen Tang, Alice Bosma-Moody, Meng Xiao He, Natalie Vokes, Jackson Nyman, Wanling Xie, Amin H. Nassar, Sarah Abou Alaiwi, Ronan Flippot, Gabrielle Bouchard, John A. Steinharter, Pier Vitale Nuzzo, Miriam Ficial, Miriam Sant'Angelo, Juliet Forman, Jacob E. Berchuck, Shaan Dudani, Kevin Bi, Jihye Park, Sabrina Camp, Maura Sticco-Ivins, Laure Hirsch, Sylvan C. Baca, Megan Wind-Rotolo, Petra Ross-Macdonald, Maxine Sun, Gwo-Shu Mary Lee, Steven L. Chang, Xiao X. Wei, Bradley A. McGregor, Lauren C. Harshman, Giannicola Genovese, Leigh Ellis, Mark Pomerantz, Michelle S. Hirsch, Matthew L. Freedman, Michael B. Atkins, Catherine J. Wu, Thai H. Ho, W. Marston Linehan, David F. McDermott, Daniel Y. C. Heng, Srinivas R. Viswanathan, Sabina Signoretti, Eliezer M. Van Allen, and Toni K. Choueiri. 2021. “Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.” Nature Communications, 12, 1, Pp. 808. Publisher's VersionAbstract
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
Kevin Bi, Meng Xiao He, Ziad Bakouny, Abhay Kanodia, Sara Napolitano, Jingyi Wu, Grace Grimaldi, David A. Braun, Michael S. Cuoco, Angie Mayorga, Laura DelloStritto, Gabrielle Bouchard, John Steinharter, Alok K. Tewari, Natalie I. Vokes, Erin Shannon, Maxine Sun, Jihye Park, Steven L. Chang, Bradley A. McGregor, Rizwan Haq, Thomas Denize, Sabina Signoretti, Jennifer L. Guerriero, Sébastien Vigneau, Orit Rozenblatt-Rosen, Asaf Rotem, Aviv Regev, Toni K. Choueiri, and Eliezer M. Van Allen. 2021. “Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma.” Cancer Cell. Publisher's Version
PURPOSE: We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC). EXPERIMENTAL DESIGN: Patients with mTNBC treated with 0-1 prior lines of chemotherapy received cisplatin 75 mg/m2 IV followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for 5 doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORRs) with a one-sided type I error of 0.1: an ORR \textgreater30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response. RESULTS: 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had BRCA2 mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% (95%CI 13-44), and median progression-free survival was 4.9 months (95%CI 2.3-5.7). Treatment-related grade 3-5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred due to sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T cell infiltration. CONCLUSIONS: Among patients with mTNBC treated with 0-1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of \textgreater30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.
The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8 T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration.
We performed harmonized molecular and clinical analysis on 1,048 melanomas and discovered markedly different global genomic properties among subtypes (BRAF, (N)RAS, NF1, triple wild-type (TWT)), subtype-specific preferences for secondary driver genes and active mutational processes previously unreported in melanoma. Secondary driver genes significantly enriched in specific subtypes reflected preferential dysregulation of additional pathways, such as induction of transforming growth factor-β signaling in BRAF melanomas and inactivation of the SWI/SNF complex in (N)RAS melanomas, and select co-mutation patterns coordinated selective response to immune checkpoint blockade. We also defined the mutational landscape of TWT melanomas and revealed enrichment of DNA-repair-defect signatures in this subtype, which were associated with transcriptional downregulation of key DNA-repair genes, and may revive previously discarded or currently unconsidered therapeutic modalities for genomically stratified melanoma patient subsets. Broadly, harmonized meta-analysis of melanoma whole exomes revealed distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.
Oksana Zavidij, Nicholas J. Haradhvala, Tarek H. Mouhieddine, Romanos Sklavenitis-Pistofidis, Songjie Cai, Mairead Reidy, Mahshid Rahmat, Abdallah Flaifel, Benjamin Ferland, Nang K. Su, Michael P. Agius, Jihye Park, Salomon Manier, Mark Bustoros, Daisy Huynh, Marzia Capelletti, Brianna Berrios, Chia-Jen Liu, Meng Xiao He, Esteban Braggio, Rafael Fonseca, Yosef E. Maruvka, Jennifer L. Guerriero, Melissa Goldman, Eliezer M. Van Allen, Steven A. McCarroll, Jamil Azzi, Gad Getz, and Irene M. Ghobrial. 2020. “Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma.” Nature Cancer, Pp. 1–14. Publisher's Version
Purpose: Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICI). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical datasets to better characterize the association between TMB and ICI response. Methods: Cohorts of NSCLC patients sequenced by one of three targeted panels or by whole exome sequencing (WES) were compared (total n=7297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z-scores. In sub-cohorts of patients treated with ICIs (DFCI n=272; MSKCC n=227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥6 months. Results: TMB values were higher in the panel cohorts than the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson coefficient 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z-scores harmonized TMB distributions and enabled integration of the ICI-treated sub-cohorts. Simulations indicated that cohorts >900 are necessary for this approach. TMB did not associate with response in never smokers or patients harboring targetable driver alterations, although these analyses were under-powered. Increasing TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operator curves yielded an area under the curve of 0.614 with no natural inflection point. Conclusion: Z-score conversion harmonizes TMB values and enables integration of datasets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB, and warrant further study.
David Liu, Bastian Schilling, Derek Liu, Antje Sucker, Elisabeth Livingstone, Livnat Jerby-Amon, Lisa Zimmer, Ralf Gutzmer, Imke Satzger, Carmen Loquai, Stephan Grabbe, Natalie Vokes, Claire A Margolis, Jake Conway, Meng Xiao He, Haitham Elmarakeby, Felix Dietlein, Diana Miao, Adam Tracy, Helen Gogas, Simone M Goldinger, Jochen Utikal, Christian U Blank, Ricarda Rauschenberg, Dagmar von Bubnoff, Angela Krackhardt, Benjamin Weide, Sebastian Haferkamp, Felix Kiecker, Ben Izar, Levi Garraway, Aviv Regev, Keith Flaherty, Annette Paschen, Eliezer M Van Allen, and Dirk Schadendorf. 2019. “Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.” Nat Med, 25, 12, Pp. 1916-1927. Publisher's VersionAbstract
Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
We present an in silico approach to identifying neoepitopes derived from intron retention events in tumor transcriptomes. Using mass spectrometry immunopeptidome analysis, we show that retained intron neoepitopes are processed and presented on MHC I on the surface of cancer cell lines. RNA-derived neoepitopes should be considered for prospective personalized cancer vaccine development.
Russell W Jenkins, Amir R Aref, Patrick H Lizotte, Elena Ivanova, Susanna Stinson, Chensheng W Zhou, Michaela Bowden, Jiehui Deng, Hongye Liu, Diana Miao, Meng Xiao He, William Walker, Gao Zhang, Tian Tian, Chaoran Cheng, Zhi Wei, Sangeetha Palakurthi, Mark Bittinger, Hans Vitzthum, Jong Wook Kim, Ashley Merlino, Max Quinn, Chandrasekar Venkataramani, Joshua A Kaplan, Andrew Portell, Prafulla C Gokhale, Bart Phillips, Alicia Smart, Asaf Rotem, Robert E Jones, Lauren Keogh, Maria Anguiano, Lance Stapleton, Zhiheng Jia, Michal Barzily-Rokni, Israel Cañadas, Tran C Thai, Marc R Hammond, Raven Vlahos, Eric S Wang, Hua Zhang, Shuai Li, Glenn J Hanna, Wei Huang, Mai P Hoang, Adriano Piris, Jean-Pierre Eliane, Anat O Stemmer-Rachamimov, Lisa Cameron, Mei-Ju Su, Parin Shah, Benjamin Izar, Manisha Thakuria, Nicole R LeBoeuf, Guilherme Rabinowits, Viswanath Gunda, Sareh Parangi, James M Cleary, Brian C Miller, Shunsuke Kitajima, Rohit Thummalapalli, Benchun Miao, Thanh U Barbie, Vivek Sivathanu, Joshua Wong, William G Richards, Raphael Bueno, Charles H Yoon, Juan Miret, Meenhard Herlyn, Levi A Garraway, Eliezer M Van Allen, Gordon J Freeman, Paul T Kirschmeier, Jochen H Lorch, Patrick A Ott, Stephen F Hodi, Keith T Flaherty, Roger D. Kamm, Genevieve M Boland, Kwok-Kin Wong, David Dornan, Cloud Peter Paweletz, and David A Barbie. 2018. “Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids.” Cancer Discov, 8, 2, Pp. 196-215. Publisher's Version
Parental care is essential for the survival of mammals, yet the mechanisms underlying its evolution remain largely unknown. Here we show that two sister species of mice, Peromyscus polionotus and Peromyscus maniculatus, have large and heritable differences in parental behaviour. Using quantitative genetics, we identify 12 genomic regions that affect parental care, 8 of which have sex-specific effects, suggesting that parental care can evolve independently in males and females. Furthermore, some regions affect parental care broadly, whereas others affect specific behaviours, such as nest building. Of the genes linked to differences in nest-building behaviour, vasopressin is differentially expressed in the hypothalamus of the two species, with increased levels associated with less nest building. Using pharmacology in Peromyscus and chemogenetics in Mus, we show that vasopressin inhibits nest building but not other parental behaviours. Together, our results indicate that variation in an ancient neuropeptide contributes to interspecific differences in parental care.