[en] The immune landscape of acute myeloid leukemia (AML) is poorly understood, and its myeloid origins complicate the distinction between pathological and immunoregulatory components. We refined the AML microenvironment (AME) classification, demonstrating distinct immunophenotypes from AML lineages and maturation stages. We developed distinct 13-gene megakaryocytic/erythroid (MK/Ery) and 16-gene myelomonocytic/monocytic (ML/Mo) polygenic markers and validated them in adult and pediatric AML patient cohorts, including single-cell RNA-sequencing data. To identify immunoregulatory factors, the AME composition was predicted by the xCell algorithm, immune dysfunction was computed by TIDE, and differential gene expression analyses identified candidate genes. To validate our findings, we studied the effects of MK/Ery-like and ML/Mo-like AML cell lines on CD8⁺ T-cells/AML cells in co-culture assays, using models identified by Celligner matching AML patient blasts. Patients with high MK/Ery expression (MK/EryHigh) exhibited a dysfunctional microenvironment with increased pro-inflammatory cytokines, increased T-cell infiltration, and upregulated immune checkpoints, particularly CD274 (PD-L1). Single-cell RNA-seq confirmed that CD274 overexpression originated from malignant subclones with MK/Ery-like phenotypes. Conversely, AML with high ML/Mo expression (ML/MoHigh) displayed a T-cell-depleted niche enriched in myeloid-derived suppressive elements, including M2 macrophages, VISTA, and galectins. MK/Ery-like (e.g., OCI-M1, HEL) and ML/Mo-like (e.g., MUTZ3, MONO-MAC-1) cells suppressed T-cell proliferation in co-culture. Pharmacological PD-1/PD-L1 blockade with the small-molecule inhibitors BMS-1166 and BMS-1001 abrogated HEL-mediated T-cell proliferation inhibition. Transcriptomic data, single-cell analyses, and functional co-culture experiments reveal two AMEs: T-cell-rich yet dysfunctional vs. myeloid-driven and immunosuppressive. This refined categorization overcomes the traditional hot-cold classification to tailor future AML immunotherapies.
Disciplines :
Hematology
Author, co-author :
Correia Da Cruz, Leslie ; Université de Liège - ULiège > GIGA ; Université de Liège - ULiège > GIGA > GIGA Immunobiology - Hematology
Lee, Yejin; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Paik, Ji Yeon; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Park, Jeonghye; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Diederich, Marc ; Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: marcdiederich@snu.ac.kr
Cerella, Claudia ✱; Laboratoire de Biologie Moléculaire du Cancer, BAM3 Pavillon 2, 6A rue Nicolas-Ernest Barblé, Luxembourg L-1210, Luxembourg. Electronic address: claudia.cerella@lbmcc.lu
✱ These authors have contributed equally to this work.
Language :
English
Title :
Bone marrow tumor microenvironment profiling predicts distinct immunosuppressive phenotypes and immunotherapy potential in AML patients.
LBMCC: \u201CRecherche Cancer et Sang\u201D foundation , the \u201CEen Ha\u0308erz fir kriibskrank Kanner\u201D , the Action LIONS \u201CVaincre le Cancer\u201D and Te\u0301le\u0301vie Luxembourg . A doctoral T\u00E9l\u00E9vie grant supported LC. CC acknowledges support from the \u201CFondation Gustave et Simone Pre\u0301vot\u201D (Geneva, Switzerland) . SNU: the \u201CRecherches Scientifiques Luxembourg\u201D association, the National Research Foundation (NRF) [Grant Number 370C-20220063 ]; MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) [Grant Number 2011-0030001 ]; Brain Korea (BK21) FOUR program and Creative-Pioneering Researchers Program at Seoul National University [Funding number: 370C-20250066 ].
van Galen, P., Hovestadt, V., Wadsworth Ii, M.H., Hughes, T.K., Griffin, G.K., Battaglia, S., Verga, J.A., Stephansky, J., Pastika, T.J., Lombardi Story, J., Pinkus, G.S., Pozdnyakova, O., Galinsky, I., Stone, R.M., Graubert, T.A., Shalek, A.K., Aster, J.C., Lane, A.A., Bernstein, B.E., Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity. Cell 176:6 (2019), 1265–1281 e24.
Yeaton, A., Cayanan, G., Loghavi, S., Dolgalev, I., Leddin, E.M., Loo, C.E., Torabifard, H., Nicolet, D., Wang, J., Corrigan, K., Paraskevopoulou, V., Starczynowski, D.T., Wang, E., Abdel-Wahab, O., Viny, A.D., Stone, R.M., Byrd, J.C., Guryanova, O.A., Kohli, R.M., Cisneros, G.A., Tsirigos, A., Eisfeld, A.K., Aifantis, I., Guillamot, M., The impact of inflammation-induced tumor plasticity during myeloid transformation. Cancer Discov. 12:10 (2022), 2392–2413.
Uhl, F.M., Chen, S., O'Sullivan, D., Edwards-Hicks, J., Richter, G., Haring, E., Andrieux, G., Halbach, S., Apostolova, P., Buscher, J., Duquesne, S., Melchinger, W., Sauer, B., Shoumariyeh, K., Schmitt-Graeff, A., Kreutz, M., Lubbert, M., Duyster, J., Brummer, T., Boerries, M., Madl, T., Blazar, B.R., Gross, O., Pearce, E.L., Zeiser, R., Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans. Sci. Transl. Med., 12(567), 2020.
Desai, P.N., Wang, B., Fonseca, A., Borges, P., Jelloul, F.Z., Reville, P.K., Lee, E., Ly, C., Basi, A., Root, J., Baran, N., Post, S.M., Deng, Q., Sun, H., Harmanci, A.O., Burks, J.K., Gomez, J.A., DiNardo, C.D., Daver, N.G., Alatrash, G., Konopleva, M., Green, M.R., Antunes, D.A., Futreal, A., Hao, D., Abbas, H.A., Single-cell profiling of CD8+ T cells in acute myeloid leukemia reveals a continuous spectrum of differentiation and clonal hyperexpansion. Cancer Immunol. Res., 2023, OF1–OF18.
Cerella, C., Dicato, M., Diederich, M., Enhancing personalized immune checkpoint therapy by immune archetyping and pharmacological targeting. Pharm. Res., 196, 2023, 106914.
Ghandi, M., Huang, F.W., Jane-Valbuena, J., Kryukov, G.V., Lo, C.C., McDonald, E.R., 3rd, Barretina, J., Gelfand, E.T., Bielski, C.M., Li, H., Hu, K., Andreev-Drakhlin, A.Y., Kim, J., Hess, J.M., Haas, B.J., Aguet, F., Weir, B.A., Rothberg, M.V., Paolella, B.R., Lawrence, M.S., Akbani, R., Lu, Y., Tiv, H.L., Gokhale, P.C., de Weck, A., Mansour, A.A., Oh, C., Shih, J., Hadi, K., Rosen, Y., Bistline, J., Venkatesan, K., Reddy, A., Sonkin, D., Liu, M., Lehar, J., Korn, J.M., Porter, D.A., Jones, M.D., Golji, J., Caponigro, G., Taylor, J.E., Dunning, C.M., Creech, A.L., Warren, A.C., McFarland, J.M., Zamanighomi, M., Kauffmann, A., Stransky, N., Imielinski, M., Maruvka, Y.E., Cherniack, A.D., Tsherniak, A., Vazquez, F., Jaffe, J.D., Lane, A.A., Weinstock, D.M., Johannessen, C.M., Morrissey, M.P., Stegmeier, F., Schlegel, R., Hahn, W.C., Getz, G., Mills, G.B., Boehm, J.S., Golub, T.R., Garraway, L.A., Sellers, W.R., Next-generation characterization of the cancer cell line encyclopedia. Nature 569:7757 (2019), 503–508.
Cerella, C., Gajulapalli, S.R., Lorant, A., Gerard, D., Muller, F., Lee, Y., Kim, K.R., Han, B.W., Christov, C., Recher, C., Sarry, J.E., Dicato, M., Diederich, M., ATP1A1/BCL2L1 predicts the response of myelomonocytic and monocytic acute myeloid leukemia to cardiac glycosides. Leukemia 38:1 (2024), 67–81.
Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., Cerami, E., Sander, C., Schultz, N., Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal, 6(269), 2013, pl1.
Goldman, M.J., Craft, B., Hastie, M., Repecka, K., McDade, F., Kamath, A., Banerjee, A., Luo, Y., Rogers, D., Brooks, A.N., Zhu, J., Haussler, D., Visualizing and interpreting cancer genomics data via the Xena platform. Nat. Biotechnol. 38:6 (2020), 675–678.
McLeod, C., Gout, A.M., Zhou, X., Thrasher, A., Rahbarinia, D., Brady, S.W., Macias, M., Birch, K., Finkelstein, D., Sunny, J., Mudunuri, R., Orr, B.A., Treadway, M., Davidson, B., Ard, T.K., Chiao, A., Swistak, A., Wiggins, S., Foy, S., Wang, J., Sioson, E., Wang, S., Michael, J.R., Liu, Y., Ma, X., Patel, A., Edmonson, M.N., Wilkinson, M.R., Frantz, A.M., Chang, T.C., Tian, L., Lei, S., Islam, S.M.A., Meyer, C., Thangaraj, N., Tater, P., Kandali, V., Ma, S., Nguyen, T., Serang, O., McGuire, I., Robison, N., Gentry, D., Tang, X., Palmer, L.E., Wu, G., Suh, E., Tanner, L., McMurry, J., Lear, M., Pappo, A.S., Wang, Z., Wilson, C.L., Cheng, Y., Meshinchi, S., Alexandrov, L.B., Weiss, M.J., Armstrong, G.T., Robison, L.L., Yasui, Y., Nichols, K.E., Ellison, D.W., Bangur, C., Mullighan, C.G., Baker, S.J., Dyer, M.A., Miller, G., Newman, S., Rusch, M., Daly, R., Perry, K., Downing, J.R., Zhang, J., St. Jude Cloud: a pediatric cancer genomic data-sharing ecosystem. Cancer Discov. 11:5 (2021), 1082–1099.
Bottomly, D., Long, N., Schultz, A.R., Kurtz, S.E., Tognon, C.E., Johnson, K., Abel, M., Agarwal, A., Avaylon, S., Benton, E., Blucher, A., Borate, U., Braun, T.P., Brown, J., Bryant, J., Burke, R., Carlos, A., Chang, B.H., Cho, H.J., Christy, S., Coblentz, C., Cohen, A.M., d'Almeida, A., Cook, R., Danilov, A., Dao, K.T., Degnin, M., Dibb, J., Eide, C.A., English, I., Hagler, S., Harrelson, H., Henson, R., Ho, H., Joshi, S.K., Junio, B., Kaempf, A., Kosaka, Y., Laderas, T., Lawhead, M., Lee, H., Leonard, J.T., Lin, C., Lind, E.F., Liu, S.Q., Lo, P., Loriaux, M.M., Luty, S., Maxson, J.E., Macey, T., Martinez, J., Minnier, J., Monteblanco, A., Mori, M., Morrow, Q., Nelson, D., Ramsdill, J., Rofelty, A., Rogers, A., Romine, K.A., Ryabinin, P., Saultz, J.N., Sampson, D.A., Savage, S.L., Schuff, R., Searles, R., Smith, R.L., Spurgeon, S.E., Sweeney, T., Swords, R.T., Thapa, A., Thiel-Klare, K., Traer, E., Wagner, J., Wilmot, B., Wolf, J., Wu, G., Yates, A., Zhang, H., Cogle, C.R., Collins, R.H., Deininger, M.W., Hourigan, C.S., Jordan, C.T., Lin, T.L., Martinez, M.E., Pallapati, R.R., Pollyea, D.A., Pomicter, A.D., Watts, J.M., Weir, S.J., Druker, B.J., McWeeney, S.K., Tyner, J.W., Integrative analysis of drug response and clinical outcome in acute myeloid leukemia. Cancer Cell 40:8 (2022), 850–864 e9.
Maiga, A., Lemieux, S., Pabst, C., Lavallee, V.P., Bouvier, M., Sauvageau, G., Hebert, J., Transcriptome analysis of G protein-coupled receptors in distinct genetic subgroups of acute myeloid leukemia: identification of potential disease-specific targets. Blood Cancer J., 6(6), 2016, e431.
Lavallee, V.P., Chagraoui, J., MacRae, T., Marquis, M., Bonnefoy, A., Krosl, J., Lemieux, S., Marinier, A., Pabst, C., Rivard, G.E., Hebert, J., Sauvageau, G., Transcriptomic landscape of acute promyelocytic leukemia reveals aberrant surface expression of the platelet aggregation agonist Podoplanin. Leukemia 32:6 (2018), 1349–1357.
Marquis, M., Beaubois, C., Lavallee, V.P., Abrahamowicz, M., Danieli, C., Lemieux, S., Ahmad, I., Wei, A., Ting, S.B., Fleming, S., Schwarer, A., Grimwade, D., Grey, W., Hills, R.K., Vyas, P., Russell, N., Sauvageau, G., Hebert, J., High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia. Blood Cancer J., 8(8), 2018, 68.
Baccelli, I., Gareau, Y., Lehnertz, B., Gingras, S., Spinella, J.F., Corneau, S., Mayotte, N., Girard, S., Frechette, M., Blouin-Chagnon, V., Leveille, K., Boivin, I., MacRae, T., Krosl, J., Thiollier, C., Lavallee, V.P., Kanshin, E., Bertomeu, T., Coulombe-Huntington, J., St-Denis, C., Bordeleau, M.E., Boucher, G., Roux, P.P., Lemieux, S., Tyers, M., Thibault, P., Hebert, J., Marinier, A., Sauvageau, G., Mubritinib targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia. Cancer Cell 36:1 (2019), 84–99 e8.
Kuusanmaki, H., Dufva, O., Vaha-Koskela, M., Leppa, A.M., Huuhtanen, J., Vanttinen, I., Nygren, P., Klievink, J., Bouhlal, J., Polonen, P., Zhang, Q., Adnan-Awad, S., Mancebo-Perez, C., Saad, J., Miettinen, J., Javarappa, K.K., Aakko, S., Ruokoranta, T., Eldfors, S., Heinaniemi, M., Theilgaard-Monch, K., Wartiovaara-Kautto, U., Keranen, M., Porkka, K., Konopleva, M., Wennerberg, K., Kontro, M., Heckman, C.A., Mustjoki, S., Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia. Blood 141:13 (2023), 1610–1625.
Aran, D., Looney, A.P., Liu, L., Wu, E., Fong, V., Hsu, A., Chak, S., Naikawadi, R.P., Wolters, P.J., Abate, A.R., Butte, A.J., Bhattacharya, M., Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20:2 (2019), 163–172.
Verhaak, R.G., Wouters, B.J., Erpelinck, C.A., Abbas, S., Beverloo, H.B., Lugthart, S., Lowenberg, B., Delwel, R., Valk, P.J., Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica 94:1 (2009), 131–134.
Tsherniak, A., Vazquez, F., Montgomery, P.G., Weir, B.A., Kryukov, G., Cowley, G.S., Gill, S., Harrington, W.F., Pantel, S., Krill-Burger, J.M., Meyers, R.M., Ali, L., Goodale, A., Lee, Y., Jiang, G., Hsiao, J., Gerath, W.F.J., Howell, S., Merkel, E., Ghandi, M., Garraway, L.A., Root, D.E., Golub, T.R., Boehm, J.S., Hahn, W.C., Defining a cancer dependency map. Cell 170:3 (2017), 564–576 e16.
Hay, S.B., Ferchen, K., Chetal, K., Grimes, H.L., Salomonis, N., The human cell atlas bone marrow single-cell interactive web portal. Exp. Hematol. 68 (2018), 51–61.
Ge, S.X., Jung, D., Yao, R., ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics 36:8 (2020), 2628–2629.
Aran, D., Hu, Z., Butte, A.J., xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol., 18(1), 2017, 220.
Maag, A.H., Swanton, H., Kull, M., Vegi, N.M., Feuring, M., Immunophenotypical profiling of myeloid neoplasms with erythroid predominance using mass cytometry (CyTOF). Cytom. A 103:7 (2023), 551–562.
Ailia, M.J., Heo, J., Yoo, S.Y., Navigating through the PD-1/PDL-1 landscape: a systematic review and meta-analysis of clinical outcomes in hepatocellular carcinoma and their influence on immunotherapy and tumor microenvironment. Int J. Mol. Sci., 24(7), 2023.
Warren, A., Chen, Y., Jones, A., Shibue, T., Hahn, W.C., Boehm, J.S., Vazquez, F., Tsherniak, A., McFarland, J.M., Global computational alignment of tumor and cell line transcriptional profiles. Nat. Commun., 12(1), 2021, 22.
Jiang, P., Gu, S., Pan, D., Fu, J., Sahu, A., Hu, X., Li, Z., Traugh, N., Bu, X., Li, B., Liu, J., Freeman, G.J., Brown, M.A., Wucherpfennig, K.W., Liu, X.S., Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med. 24:10 (2018), 1550–1558.
Cerella, C., Gaigneaux, A., Mazumder, A., Lee, J.Y., Saland, E., Radogna, F., Farge, T., Vergez, F., Recher, C., Sarry, J.E., Kim, K.W., Shin, H.Y., Dicato, M., Diederich, M., Bcl-2 protein family expression pattern determines synergistic pro-apoptotic effects of BH3 mimetics with hemisynthetic cardiac glycoside UNBS1450 in acute myeloid leukemia. Leukemia 31:3 (2017), 755–759.
Mazumder, A., Lee, J.Y., Talhi, O., Cerella, C., Chateauvieux, S., Gaigneaux, A., Hong, C.R., Kang, H.J., Lee, Y., Kim, K.W., Kim, D.W., Shin, H.Y., Dicato, M., Bachari, K., Silva, A.M.S., Orlikova-Boyer, B., Diederich, M., Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release. Cancer Lett. 438 (2018), 197–218.
Terren, I., Orrantia, A., Vitalle, J., Zenarruzabeitia, O., Borrego, F., CFSE dilution to study human T and NK cell proliferation in vitro. Methods Enzym. 631 (2020), 239–255.
Nusinow, D.P., Szpyt, J., Ghandi, M., Rose, C.M., McDonald, E.R., 3rd, Kalocsay, M., Jane-Valbuena, J., Gelfand, E., Schweppe, D.K., Jedrychowski, M., Golji, J., Porter, D.A., Rejtar, T., Wang, Y.K., Kryukov, G.V., Stegmeier, F., Erickson, B.K., Garraway, L.A., Sellers, W.R., Gygi, S.P., Quantitative proteomics of the cancer cell line encyclopedia. Cell 180:2 (2020), 387–402 e16.
Combes, A.J., Samad, B., Tsui, J., Chew, N.W., Yan, P., Reeder, G.C., Kushnoor, D., Shen, A., Davidson, B., Barczak, A.J., Adkisson, M., Edwards, A., Naser, M., Barry, K.C., Courau, T., Hammoudi, T., Arguello, R.J., Rao, A.A., Olshen, A.B., Immunoprofiler, C., Cai, C., Zhan, J., Davis, K.C., Kelley, R.K., Chapman, J.S., Atreya, C.E., Patel, A., Daud, A.I., Ha, P., Diaz, A.A., Kratz, J.R., Collisson, E.A., Fragiadakis, G.K., Erle, D.J., Boissonnas, A., Asthana, S., Chan, V., Krummel, M.F., Discovering dominant tumor immune archetypes in a pan-cancer census. Cell 185:1 (2022), 184–203 e19.
Sallman, D.A., McLemore, A.F., Aldrich, A.L., Komrokji, R.S., McGraw, K.L., Dhawan, A., Geyer, S., Hou, H.A., Eksioglu, E.A., Sullivan, A., Warren, S., MacBeth, K.J., Meggendorfer, M., Haferlach, T., Boettcher, S., Ebert, B.L., Al Ali, N.H., Lancet, J.E., Cleveland, J.L., Padron, E., List, A.F., TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype. Blood 136:24 (2020), 2812–2823.
Zeidan, A.M., Boss, I., Beach, C.L., Copeland, W.B., Thompson, E., Fox, B.A., Hasle, V.E., Ogasawara, K., Cavenagh, J., Silverman, L.R., Voso, M.T., Hellmann, A., Tormo, M., O'Connor, T., Previtali, A., Rose, S., Garcia-Manero, G., A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes. Blood Adv. 6:7 (2022), 2207–2218.
Dohner, H., Wei, A.H., Appelbaum, F.R., Craddock, C., DiNardo, C.D., Dombret, H., Ebert, B.L., Fenaux, P., Godley, L.A., Hasserjian, R.P., Larson, R.A., Levine, R.L., Miyazaki, Y., Niederwieser, D., Ossenkoppele, G., Rollig, C., Sierra, J., Stein, E.M., Tallman, M.S., Tien, H.F., Wang, J., Wierzbowska, A., Lowenberg, B., Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140:12 (2022), 1345–1377.
Gerds, A.T., Scott, B.L., Greenberg, P., Lin, T.L., Pollyea, D.A., Verma, A., Dail, M., Feng, Y., Green, C., Ma, C., Medeiros, B.C., Yan, M., Yousefi, K., Donnellan, W., Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. Blood Adv. 6:4 (2022), 1152–1161.
Mumme, H., Thomas, B.E., Bhasin, S.S., Krishnan, U., Dwivedi, B., Perumalla, P., Sarkar, D., Ulukaya, G.B., Sabnis, H.S., Park, S.I., DeRyckere, D., Raikar, S.S., Pauly, M., Summers, R.J., Castellino, S.M., Wechsler, D.S., Porter, C.C., Graham, D.K., Bhasin, M., Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia. Nat. Commun., 14(1), 2023, 6209.
