A main goal in the Greenbaum lab is to quantify how the immune system is activated and how it impacts tumor evolution. A particular focus in the lab is the role of repetitive elements in the genome, which mimic viral features and, just like viruses, evolve to escape immune surveillance. Dr. Greenbaum developed the first models to quantify this ‘viral mimicry’, molecular patterns reminiscent of pathogens that can activate the innate immune system (Greenbaum et al. PNAS 2014; Solovyov et al. Cell Reports 2018). These data recently contributed to a phase II clinical trial of 3TC, a reverse transcriptase inhibitor that prevented the activation of retrotransposons in patients with metastatic colorectal cancer and showed clinical benefits in 9 of 32 patients (Rajurkar et al. Cancer Discovery 2022). Viral mimics play an underappreciated role in tumor evolution and Dr. Greenbaum’s work reveals new vulnerabilities to be exploited. Within the last few years Dr. Greenbaum’s group and his collaborators also created models to predict the role of neoantigens in tumor evolution, and they established the concept of ‘neoantigen quality’ to assess the likelihood that a neoantigen will induce an immune response (Luksza et al. Nature, 2022). Models that contributed to motivating a recent phase I clinical trial (Rojas et al. Nature 2023). His team discovered an immune tradeoff in cancer evolution: oncogenic mutations with lower fitness present poorly to the immune system, while mutations with high fitness generate potent neoantigens (Hoyos et al. Nature 2022). The goal of Immuno-Oncology is to act as a bridge between Computational Oncology and other investigators and clinicians in immuno-oncology at MSK, with the ultimate aim to use the power of the immune system to fight cancer.
View available career opportunities in the lab here.
Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, Lihm J, Ceglia N, Guasp P, Chu A, Yu R, Chandra AK, Waters T, Ruan J, Amisaki M, Zebboudj A, Odgerel Z, Payne G, Derhovanessian E, Müller F, Rhee I, Yadav M, Dobrin A, Sadelain M, Łuksza M, Cohen N, Tang L, Basturk O, Gönen M, Katz S, Do RK, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D’Angelica MI, Kingham TP, Mellman I, Merghoub T, Wolchok JD, Sahin U, Türeci Ö, Greenbaum BD*, Jarnagin WR, Drebin J, O’Reilly EM, Balachandran VP*. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023 Jun;618(7963):144-150. PMCID: PMC10171177.
Hoyos D, Zappasodi R, Schulze I, Sethna Z, de Andrade KC, Bajorin DF, Bandlamudi C, Callahan MK, Funt SA, Hadrup SR, Holm JS, Rosenberg JE, Shah SP, Vázquez-García I, Weigelt B, Wu M, Zamarin D, Campitelli LF, Osborne EJ, Klinger M, Robins HS, Khincha PP, Savage SA, Balachandran VP, Wolchok JD, Hellmann MD, Merghoub T, Levine AJ, Łuksza M, Greenbaum BD*. Fundamental immune-oncogenicity trade-offs define driver fitness. Nature. 2022 Jun;606(7912):172–179. PMCID: PMC9159948
Łuksza M, Sethna ZM, Rojas LA, Lihm J, Bravi B, Elhanati Y, Soares K, Amisaki M, Dobrin A, Hoyos D, Guasp P, Zebboudj A, Yu R, Chandra AK, Waters T, Odgerel Z, Leung J, Kappagantula R, Makohon-Moore A, Johns A, Gill A, Gigoux M, Wolchok J, Merghoub T, Sadelain M, Patterson E, Monasson R, Mora T, Walczak AM, Cocco S, Iacobuzio-Donahue C, Greenbaum BD*, Balachandran VP*. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature. 2022 Jun;606(7913):389–395. PMID: PMC35589842
Lyudovyk O, Kim JY, Qualls D, Hwee MA, Lin YH, Boutemine SR, Elhanati Y, Solovyov A, Douglas M, Chen E, Babady NE, Ramanathan L, Vedantam P, Bandlamudi C, Gouma S, Wong P, Hensley SE, Greenbaum BD*, Huang AC, Vardhana SA*. Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses. Cancer Cell. 2022 Jul;40(7):738-753.e5. PMCID: PMC9149241.
Porter RL, Sun S, Flores MN, Berzolla E, You E, Phillips IE, Kc N, Desai N, Tai EC, Szabolcs A, Lang ER, Pankaj A, Raabe MJ, Thapar V, Xu KH, Nieman LT, Rabe DC, Kolin DL, Stover EH, Pepin D, Stott SL, Deshpande V, Liu JF, Solovyov A, Matulonis UA, Greenbaum BD*, Ting DT*. Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype. J Clin Invest. 2022 Aug;132(16). PMCID: PMC9374379
Rajurkar M, Parikh AR, Solovyov A, You E, Kulkarni AS, Chu C, Xu KH, Jaicks C, Taylor MS, Wu C, Alexander KA, Good CR, Szabolcs A, Gerstberger S, Tran AV, Xu N, Ebright RY, Van Seventer EE, Vo KD, Tai EC, Lu C, Joseph-Chazan J, Raabe MJ, Nieman LT, Desai N, Arora KS, Ligorio M, Thapar V, Cohen L, Garden PM, Senussi Y, Zheng H, Allen JN, Blaszkowsky LS, Clark JW, Goyal L, Wo JY, Ryan DP, Corcoran RB, Deshpande V, Rivera MN, Aryee MJ, Hong TS, Berger SL, Walt DR, Burns KH, Park PJ, Greenbaum BD*, Ting DT*. Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer. Cancer Discov. 2022 Jun;12(6):1462–1481. PMCID: PMC9167735
Hoyos D, Greenbaum BD*. Perfecting antigen prediction. J Exp Med. 2022 Sep;219(9). PMCID: PMC9386507
Hoyos D, Greenbaum BD, Levine AJ. The genotypes and phenotypes of missense mutations in the proline domain of the p53 protein. Cell Death Differ. 2022 May;(5):938–945. PMCID: PMC9090814
Bravi B, Balachandran VP, Greenbaum BD, Walczak AM, Mora T, Monasson R, Cocco S. Probing T-cell response by sequence-based probabilistic modeling. PLoS Comput Biol. 2021 Sep;(9):e1009297. PMCID: PMC8476001
Roudko V, Cimen Bozkus C, Greenbaum BD, Lucas A, Samstein R, Bhardwaj N. Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines. Front Immunol. 2021 Sep;12:757804. PMCID: PMC8498209.
[* denotes Corresponding author]
CompIO – As cancer immunotherapies have emerged as front-line therapies, it has become clear that advancing computational approaches to cancer immunology is critical to better understanding the role of the immune system in cancer. Despite the enormous promise of immunotherapy, success is still limited to a minority of patients and tumor types. Through a better quantitative understanding of how immunotherapies work and how the immune system reacts to them, the Program in Computational Immuno-Oncology hopes to play a role in extending the benefit of immunotherapies to a larger set of patients, and in gaining new insights on malignant-immune cell interactions. Several next-generation computational approaches to understanding tumor evolution are being advanced in the Computational Oncology Service. At the same time, there have been significant advances in high-resolution quantitative immunology and the immune driven evolution of pathogens which should be brought into cancer research areas such as response to immunotherapy and the role of immune system in the tumor microenvironment. Our Program aims to bring such approaches to bear on problems in cancer immunology and immunotherapy by bridging the Computational Oncology Service and the Parker Institute for Cancer Immunotherapy.
Please visit Dr. Greenbaum’s faculty page, PubMed or Google Scholar for more publications.
