Immuno-Oncology | Greenbaum – Computational Oncology

Self vs Non-Self Recognition in Cancer Immunity

Greenbaum Lab

The Greenbaum Lab harnesses fundamental principles of self vs. non-self discrimination to improve cancer immunotherapy and vaccine design. Our core insight: the immune system’s ability to distinguish tumor-derived antigens from normal self-tissue can be quantified, modeled, and exploited therapeutically.

CLINICAL TRANSLATION

Our self–nonself framework directly informs therapeutic development:

Personalized Vaccine

Neoantigen quality models guided a phase I RNA vaccine trial in pancreatic cancer Rojas et al., Nature 2023; Sethna et al., Nature 2025 and underpin numerous ongoing trials.

Prophylactic Vaccines

Shared germline neo-antigens in Lynch and Li-Fraumeni syndromes open the door to off-the-shelf cancer prevention vaccines (Roudko et al., Cell 2020; Hoyos et al., 2022).

Dark Genome Therapeutics

Retrotransposon inhibition via reverse transcriptase inhibitors showed clinical benefit in metastatic colorectal cancer (Rajurkar et al., Cancer Discovery 2022; Baldwin et al., Nature 2024).

CORE RESEARCH

Neoantigen Quality

We introduced the concept of neoantigen quality — biophysical features quantifying how likely a cancer neoantigen is to be seen as non-self by T cells (Lłuksza et al., Nature 2017; Balachandran et al., Nature 2017). These models were extended to predict how neoantigen quality and driver mutations shape tumor-immune co-evolution (Lłuksza et al., Nature 2022).

Evolutionary Trade-offs

Driver mutations present a fundamental tension: they boost tumor growth but can render cells more visible as non-self. Using a free-fitness framework analogous to statistical physics, we quantified this trade-off (Hoyos et al., Nature 2022). Retrotransposons similarly modulate innate immunity in trade-offs with drivers like p53 (Sun et al., Immunity 2024).

Retrotransposons in Cancer & Immunity

Over 50% of the human genome is repetitive, with many elements acting as viral mimics flagged by innate immunity. We showed LINE-1 activates the STING-cGAS pathway and completed the largest whole-genome study of LINE-1 retrotransposition in cancer (Baldwin et al., Nature 2024; Solovyov et al., Nat. Comm. 2025).

Recent Publications

2026

How Different are Self and Nonself?

Tiffeau-Mayer, J. A. Levine, C. J. Russo, Q. Marcou, W. Bialek and B. D. GreenbaumPRX Life 2026 Vol. 4 Issue 1 Pages 013027DOI: 10.1103/fbct-vzwm

DOI: https://doi.org/10.1103/fbct-vzwm

2025

RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer

Sethna Z, Guasp P, Reiche C, Milighetti M, Ceglia N, Patterson E, Lihm J, Payne G, Lyudovyk O, Rojas LA, Pang N, Ohmoto A, Amisaki M, Zebboudj A, Odgerel Z, Bruno EM, Zhang SL, Cheng C, Elhanati Y, Derhovanessian E, Manning L, Müller F, Rhee I, Yadav M, Merghoub T, Wolchok JD, Basturk O, Gönen M, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D’Angelica MI, Kingham TP, Soares KC, Jarnagin WR, Drebin J, O’Reilly EM, Mellman I, Sahin U, Türeci Ö, Greenbaum BD*, Balachandran VP*

Nature. 2025 Mar;639(8056):1042–1051.

PMCID: PMC11946889

Pan-cancer multi-omic model of LINE-1 activity reveals locus heterogeneity of retrotransposition efficiency

Solovyov A, Behr JM, Hoyos D, Banks E, Drong AW, Thornlow B, Zhong JZ, Garcia-Rivera E, McKerrow W, Chu C, Arisdakessian C, Zaller DM, Kamihara J, Diao L, Fromer M, Greenbaum BD*

Nat Commun. 2025 Feb 28;16(1):2049.

PMCID: PMC11871128

Repeats mimic pathogen-associated patterns across a vast evolutionary landscape

Šulc P, Di Gioacchino A, Solovyov A, Sun S, Martis S, Marhon SA, Lindholm HT, Chen R, Hosseini A, Jiang H, Ly BH, Taylor MS, Mehdipour P, Abdel-Wahab O, Rusk N, Vabret N, LaCava J, De Carvalho DD, Monasson R, Cocco S, Greenbaum BD*

Cell Genom. 2025 Dec 10;5(12):101011.

PMID: 40997813

2024

Structures, functions and adaptations of the human LINE-1 ORF2 protein

Baldwin ET, van Eeuwen T, Hoyos D, Zalevsky A, Tchesnokov EP, Sánchez R, Miller BD, Di Stefano LH, Ruiz FX, Hancock M, Işik E, Mendez-Dorantes C, Walpole T, Nichols C, Wan P, Riento K, Halls-Kass R, Augustin M, Lammens A, Jestel A, Upla P, Xibinaku K, Congreve S, Hennink M, Rogala KB, Schneider AM, Fairman JE, Christensen SM, Desrosiers B, Bisacchi GS, Saunders OL, Hafeez N, Miao W, Kapeller R, Zaller DM, Sali A, Weichenrieder O, Burns KH, Götte M, Rout MP, Arnold E, Greenbaum BD, Romero DL, LaCava J, Taylor MS

Nature. 2024 Feb;626(7997):194–206.

PMID: 38096902 · PMCID: PMC10830420

Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms

Sun S, You E, Hong J, Hoyos D, Del Priore I, Tsanov KM, Mattagajasingh O, Di Gioacchino A, Marhon SA, Chacon-Barahona J, Li H, Jiang H, Hozeifi S, Rosas-Bringas O, Xu KH, Song Y, Lang ER, Rojas AS, Nieman LT, Patel BK, Murali R, Chanda P, Karacay A, Vabret N, De Carvalho DD, Zenklusen D, LaCava J, Lowe SW, Ting DT, Iacobuzio-Donahue CA, Solovyov A, Greenbaum BD*

Immunity. 2024 Dec 10;57(12):2879–2894.e11.

PMCID: PMC12022969

2023

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

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*

Nature. 2023 Jun;618(7963):144–150.

PMCID: PMC10171177

2022

Fundamental immune-oncogenicity trade-offs define driver fitness

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*

Nature. 2022 Jun;606(7912):172–179.

PMCID: PMC9159948

Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

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*

Nature. 2022 Jun;606(7913):389–395.

PMCID: PMC35589842

Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

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*

Cancer Discov. 2022 Jun;12(6):1462–1481.

PMCID: PMC9167735