Sachet A. Shukla, PhD, MS
Department of Hematopoietic Biology & Malignancy, Division of Cancer Medicine
Present Title & Affiliation
Assistant Professor, Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Assistant Professor, Department of Immunology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX
My research studies focus on elucidating the role of the immune system in cancer biology and discovery of novel immunotherapeutic targets through development of immunogenomic approaches. Genomic analysis of immune related genes has traditionally been error-prone due to their high degree of diversity in the population. To address this problem I have developed a computational method called Polysolver for accurate typing and mutation detection in the highly polymorphic human leukocyte antigen (HLA) genes using next-generation sequencing (NGS) data ( Nat Biotech, 2015 ). This tool has been shown to have superlative performance characteristics and has been instrumental in characterizing patient immunophenotypes in many different cancer studies. Neoantigen based cancer vaccines constitute a novel immunotherapeutic paradigm that recruit tumor-specific cytotoxic immune responses against cancer specific peptides. I have developed a computational pipeline for the rational design of neoantigen-based vaccines ( Blood, 2014 ) which has already been used in two first-in-man clinical trials at Dana-Farber Cancer Institute ( Nature, 2017; Nature, 2019 ). The neoantigen prediction pipeline, in conjunction with the Polysolver tool, has also led to the identification of immunological correlates of several biological and clinical features in various tumor types ( JAMA Onc, 2015; Nat Genetics, 2016; Cell Rep, 2016; Immunity, 2017 ). I have supervised the development of a computational pipeline for quantification of endogenous retroviruses (ERVs) in the human genome, which has identified some potentially targetable antigen targets ( Nat Med, 2020 ). A second major focus of my work has been in delineating mechanisms of response and resistance to immune therapies, particularly checkpoint blockade ( Science, 2015; JAMA Onc, 2019; Nat Med 2020 ). I have recently spearheaded a multi-institutional project which uncovered a novel expression signature of resistance to anti-CTLA4 therapy in metastatic melanoma with significant clinical implications ( Cell, 2018 ). I have previously identified a metabolomic signature of response to PD-1 blockade in renal cancer and am currently developing methods for integrating metabolomic data with matched genomic, transcriptomic and immunostaining profiles ( Nat Comm, 2019 ). I have developed pipelines for bulk and single cell T-cell receptor sequencing analysis which are currently being used in several ongoing studies designed to address fundamental questions in T-cell biology ( Nature Protoc, 2019 ).
Education & Training
|2014||Iowa State University, Ames, IA, USA, PHD, Bioinformatics and Statistics|
|2006||Iowa State University, Ames, IA, USA, MS, Statistics|
|2003||Iowa State University, Ames, IA, USA, MS, Bioinformatics and Computational Biology|
|2000||University of Pune, Pune, IND, Advanced Diploma, Bioinformatics|
|1999||Indian Institute of Technology, Kharagpur, IND, Bachelor of Technology, Chemical Engineering|
Experience & Service
Director, Computational Biology ECLIPSE, The University of Texas MD Anderson Cancer Center, Houston, 2021 - Present
Computational Lead Scientist, Dana-Farber Cancer Institute, Boston, MA, 2018 - 2021
Senior Scientist, Dana-Farber Cancer Institute, Boston, MA, 2014 - 2018
Scientist II, Dana-Farber Cancer Institute, Boston, MA, 2012 - 2014
Research Scientist, Dana-Farber Cancer Institute, Boston, MA, 2010 - 2012
Research Analyst II, Dana-Farber Cancer Institute, Boston, MA, 2008 - 2010
Computational Biologist, NewLink Genetics, Ames, IA, 2000 - 2008
Honors & Awards
|2016||NCI Research Specialist Award, NIH-NCI|
|2008||Highly cited researcher, Web of Science|
|2005||L.H. Baker graduate award, Statistics Department, Iowa State University|
|2000||Premium for Academic Excellence Award, Iowa State University|
|2000||Bioinformatics and Computational Biology departmental fellowship, Iowa State University|
|1999||Department of Biotechnology Fellowship, Government of India|
- Braun DA, Hou Y, Bakouny Z, Ficial M, Sant' Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, Steinharter J, Sun M, Wind-Rotolo M, Pignon JC, Cherniack AD, Lichtenstein L, Neuberg D, Catalano P, Freeman GJ, Sharpe AH, McDermott DF, Van Allen EM, Signoretti S, Wu CJ, Shukla SA, Choueiri TK. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med 26(6):909-918, 2020. e-Pub 2020. PMID: 32472114.
- Braun DA, Ishii Y, Walsh AM, Van Allen EM, Wu CJ, Shukla SA, Choueiri TK. Clinical Validation of PBRM1 Alterations as a Marker of Immune Checkpoint Inhibitor Response in Renal Cell Carcinoma. JAMA Oncol 5(11):1631-1633, 2019. PMID: 31486842.
- Li H, Bullock K, Gurjao C, Braun D, Shukla SA, Bossé D, Lalani AA, Gopal S, Jin C, Horak C, Wind-Rotolo M, Signoretti S, McDermott DF, Freeman GJ, Van Allen EM, Schreiber SL, Stephen Hodi F, Sellers WR, Garraway LA, Clish CB, Choueiri TK, Giannakis M. Metabolomic adaptations and correlates of survival to immune checkpoint blockade. Nat Commun 10(1):4346, 2019. e-Pub 2019. PMID: 31554815.
- Li S, Sun J, Allesøe R, Datta K, Bao Y, Oliveira G, Forman J, Jin R, Olsen LR, Keskin DB, Shukla SA, Wu CJ, Livak KJ. RNase H-dependent PCR-enabled T-cell receptor sequencing for highly specific and efficient targeted sequencing of T-cell receptor mRNA for single-cell and repertoire analysis. Nat Protoc 14(8):2571-2594, 2019. e-Pub 2019. PMID: 31341290.
- Mahoney KM, Shukla SA, Patsoukis N, Chaudhri A, Browne EP, Arazi A, Eisenhaure TM, Pendergraft WF, Hua P, Pham HC, Bu X, Zhu B, Hacohen N, Fritsch EF, Boussiotis VA, Wu CJ, Freeman GJ. A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression. Cancer Immunol Immunother 68(3):421-432, 2019. e-Pub 2018. PMID: 30564891.
- Shukla SA, Bachireddy P, Schilling B, Galonska C, Zhan Q, Bango C, Langer R, Lee PC, Gusenleitner D, Keskin DB, Babadi M, Mohammad A, Gnirke A, Clement K, Cartun ZJ, Van Allen EM, Miao D, Huang Y, Snyder A, Merghoub T, Wolchok JD, Garraway LA, Meissner A, Weber JS, Hacohen N, Neuberg D, Potts PR, Murphy GF, Lian CG, Schadendorf D, Hodi FS, Wu CJ. Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade. Cell 173(3):624-633.e8, 2018. e-Pub 2018. PMID: 29656892.
- Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Salazar AM, Daley H, Seaman M, Buchbinder EI, Yoon CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N, Wu CJ. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547(7662):217-221, 2017. e-Pub 2017. PMID: 28678778.
- Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, Bahl S, Cao Y, Amin-Mansour A, Yamauchi M, Sukawa Y, Stewart C, Rosenberg M, Mima K, Inamura K, Nosho K, Nowak JA, Lawrence MS, Giovannucci EL, Chan AT, Ng K, Meyerhardt JA, Van Allen EM, Getz G, Gabriel SB, Lander ES, Wu CJ, Fuchs CS, Ogino S, Garraway LA. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep 15(4):857-865, 2016. e-Pub 2016. PMID: 27149842.
- Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, Stover E, Strickland KC, D'Andrea AD, Wu CJ, Matulonis UA, Konstantinopoulos PA. Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1. JAMA Oncol 1(9):1319-23, 2015. PMID: 26181000.
- Shukla SA, Rooney MS, Rajasagi M, Tiao G, Dixon PM, Lawrence MS, Stevens J, Lane WJ, Dellagatta JL, Steelman S, Sougnez C, Cibulskis K, Kiezun A, Hacohen N, Brusic V, Wu CJ, Getz G. Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat Biotechnol 33(11):1152-8, 2015. PMID: 26372948.
- Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160(1-2):48-61, 2015. PMID: 25594174.
- Rajasagi M, Shukla SA, Fritsch EF, Keskin DB, DeLuca D, Carmona E, Zhang W, Sougnez C, Cibulskis K, Sidney J, Stevenson K, Ritz J, Neuberg D, Brusic V, Gabriel S, Lander ES, Getz G, Hacohen N, Wu CJ. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124(3):453-62, 2014. e-Pub 2014. PMID: 24891321.
- Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, Sougnez C, Stewart C, Sivachenko A, Wang L, Wan Y, Zhang W, Shukla SA, Vartanov A, Fernandes SM, Saksena G, Cibulskis K, Tesar B, Gabriel S, Hacohen N, Meyerson M, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152(4):714-26, 2013. PMID: 23415222.
- Genovese G, Ergun A, Shukla SA, Campos B, Hanna J, Ghosh P, Quayle SN, Rai K, Colla S, Ying H, Wu CJ, Sarkar S, Xiao Y, Zhang J, Zhang H, Kwong L, Dunn K, Wiedemeyer WR, Brennan C, Zheng H, Rimm DL, Collins JJ, Chin L. microRNA regulatory network inference identifies miR-34a as a novel regulator of TGF-β signaling in glioblastoma. Cancer Discov 2(8):736-49, 2012. e-Pub 2012. PMID: 22750848.
- Chen AJ, Paik JH, Zhang H, Shukla SA, Mortensen R, Hu J, Ying H, Hu B, Hurt J, Farny N, Dong C, Xiao Y, Wang YA, Silver PA, Chin L, Vasudevan S, Depinho RA. STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA. Genes Dev 26(13):1459-72, 2012. PMID: 22751500.
Grant & Contract Support
|Title:||Personal tumor neoantigens for immunity against chronic lymphocytic leukemia|
|Title:||Combining Locally Administered Ipilimumab with a Personalized Neoantigen Cancer Vaccine to Improve T-Cell Priming and Antitumor Immunity in High-Risk Renal Cell Carcinoma|
|Funding Source:||Department of Defense (DOD)|
|Title:||Biomaterials to Create T Cell Immunity|
|Title:||Immunogenomic analytical approaches for research and clinical applications|
|Title:||Using Single-Cell Transcriptomics to Understand Tumor and Immune Heterogeneity Driving Resistance to Immune Therapy in Advanced RCC|
|Funding Source:||Department of Defense (DOD)|
|Title:||Tissue-based predictive biomarkers for Cabozantinib therapy in metastatic renal cell carcinoma|
|Title:||DF/HCC Kidney Cancer SPORE|
|Title:||Discovery of antigen targets for cancer immunotherapy|
|Funding Source:||Cancer Prevention & Research Institute of Texas (CPRIT)|