Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoid malignancy associated with a poor clinical prognosis. The AITL tumor microenvironment (TME) is unique, featuring a minority population of malignant CD4+ T follicular helper (TFH) cells inter-mixed with a diverse infiltrate of multi-lineage immune cells. While much of the understanding of AITL biology to date has focused on characteristics of the malignant clone, less is known about the many non-malignant populations that comprise the TME. Recently, mutational consistencies have been identified between malignant cells and non-malignant B cells within the AITL TME. As a result, a significant role for non-malignant populations in AITL biology has been increasingly hypothesized. In this study, we have utilized mass cytometry and single-cell transcriptome analysis to identify several expanded populations within the AITL TME. Notably, we find that B cells within the AITL TME feature decreased expression of key markers including CD73 and CXCR5. Furthermore, we describe the expansion of distinct CD8+ T cell populations that feature an exhausted phenotype and an underlying expression profile indicative of dysfunction, impaired cytotoxicity, and upregulation of the chemokines XCL2 and XCL1.
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Lunning MA, Vose JM. Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma. Blood. 2017;129:1095–102.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.
Federico M, Rudiger T, Bellei M, Nathwani BN, Luminari S, Coiffier B, et al. Clinicopathologic characteristics of angioimmunoblastic T-Cell lymphoma: analysis of the international peripheral T-cell lymphoma project. J Clin Oncol. 2013;31:240–6.
Mhaidly R, Krug A, Gaulard P, Lemonnier F, Ricci J-E, Verhoeyen E New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP. Oncogenesis. 2020; 9. https://doi.org/10.1038/s41389-020-00259-x.
Chiba S, Sakata-Yanagimoto M. Advances in understanding of angioimmunoblastic T-cell lymphoma. Leukemia. 2020;34:2592–606.
Lachenal F, Berger F, Ghesquières H, Biron P, Hot A, Callet-Bauchu E, et al. Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients. Medicine. 2007;86:282–92.
Gaulard P, de Leval L. The microenvironment in T-cell lymphomas: emerging themes. Semin Cancer Biol. 2014;24:49–60.
Palomero T, Couronné L, Khiabanian H, Kim M-Y, Ambesi-Impiombato A, Perez-Garcia A, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46:166–70.
Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:171–5.
Yoo HY, Sung MK, Lee SH, Kim S, Lee H, Park S, et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:371–5.
Lemonnier F, Cairns RA, Inoue S, Li WY, Dupuy A, Broutin S, et al. The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development. Proc Natl Acad Sci USA. 2016;113:15084–9.
Ng SY, Brown L, Stevenson K, deSouza T, Aster JC, Louissaint A, et al. RhoA G17V is sufficient to induce autoimmunity and promotes T-cell lymphomagenesis in mice. Blood. 2018;132:935–47.
Schwartz FH, Cai Q, Fellmann E, Hartmann S, Mäyränpää MI, Karjalainen-Lindsberg M-L, et al. TET2 mutations in B cells of patients affected by angioimmunoblastic T-cell lymphoma. J Pathol. 2017;242:129–33.
Lemonnier F, Mak TW. Angioimmunoblastic T-cell lymphoma: more than a disease of T follicular helper cells. J Pathol. 2017;242:387–90.
Yao W-Q, Wu F, Zhang W, Chuang S-S, Thompson JS, Chen Z, et al. Angioimmunoblastic T-cell lymphoma contains multiple clonal T-cell populations derived from a common TET2 mutant progenitor cell. J Pathol. 2020;250:346–57.
Cader FZ, Schackmann RCJ, Hu X, Wienand K, Redd R, Chapuy B, et al. Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment. Blood. 2018;132:825–36.
Neeland MR, Andorf S, Manohar M, Dunham D, Lyu S-C, Dang TD, et al. Mass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life. Nat Commun. 2020;11:1091.
Kudryavtsev I, Serebriakova M, Starshinova A, Zinchenko Y, Basantsova N, Malkova A, et al. Imbalance in B cell and T follicular helper cell subsets in pulmonary sarcoidosis. Sci Rep. 2020;10:1059.
Verma K, Ogonek J, Varanasi PR, Luther S, Bünting I, Thomay K, et al. Human CD8+ CD57- TEMRA cells: Too young to be called ‘old’. PloS ONE. 2017;12:e0177405.
Maggi L, Santarlasci V, Capone M, Rossi MC, Querci V, Mazzoni A, et al. Distinctive features of classic and nonclassic (Th17 derived) human Th1 cells. Eur J Immunol. 2012;42:3180–8.
Yang Z-Z, Kim HJ, Villasboas JC, Price-Troska T, Jalali S, Wu H, et al. Mass cytometry analysis reveals that specific intratumoral CD4+ T cell subsets correlate with patient survival in follicular lymphoma. Cell Rep. 2019;26:2178–2193.e3.
Kotecha N, Krutzik PO, Irish JM. Web-based analysis and publication of flow cytometry experiments. Curr Protoc Cytom. 2010;10, https://doi.org/10.1002/0471142956.cy1017s53.
Amir ED, Davis KL, Tadmor MD, Simonds EF, Levine JH, Bendall SC, et al. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol. 2013;31:545–52.
Amir E-AD, Lee B, Badoual P, Gordon M, Guo XV, Merad M, et al. Development of a comprehensive antibody staining database using a standardized analytics pipeline. Front Immunol. 2019;10:1315.
Li H, van der Leun AM, Yofe I, Lubling Y, Gelbard-Solodkin D, van Akkooi ACJ, et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell. 2019;176:775–789.e18.
Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M, Dimeloe S, et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med. 2018;24:994–1004.
Jansen CS, Prokhnevska N, Master VA, Sanda MG, Carlisle JW, Bilen MA, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature. 2019;576:465–70.
Nicolet BP, Guislain A, van Alphen FPJ, Gomez-Eerland R, Schumacher TNM, van den Biggelaar M, et al. CD29 identifies IFN-γ-producing human CD8+ T cells with an increased cytotoxic potential. Proc Natl Acad Sci USA. 2020;117:6686–96.
Fox JC, Nakayama T, Tyler RC, Sander TL, Yoshie O, Volkman BF. Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily. Cytokine. 2015;71:302–11.
Rhodes JW, Tong O, Harman AN, Turville SG. Human dendritic cell subsets, ontogeny, and impact on HIV infection. Front Immunol. 2019;10:1088.
Lei Y, Takahama Y. XCL1 and XCR1 in the immune system. Microbes Infect. 2012;14:262–7.
Kroczek RA, Henn V. The role of XCR1 and its ligand XCL1 in antigen cross-presentation by murine and human dendritic cells. Front Immunol. 2012;3:14.
Ohta T, Sugiyama M, Hemmi H, Yamazaki C, Okura S, Sasaki I, et al. Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in intestinal immune homeostasis. Sci Rep. 2016;6:23505.
Mizumoto Y, Hemmi H, Katsuda M, Miyazawa M, Kitahata Y, Miyamoto A, et al. Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade. Br J Cancer. 2020;122:1185–93.
Troxell ML, Schwartz EJ, van de Rijn M, Ross DT, Warnke RA, Higgins JP, et al. Follicular dendritic cell immunohistochemical markers in angioimmunoblastic T-cell lymphoma. Appl Immunohistochem Mol Morphol AIMM. 2005;13:297–303.
Aguzzi A, Kranich J, Krautler NJ. Follicular dendritic cells: origin, phenotype, and function in health and disease. Trends Immunol. 2014;35:105–13.
Kim E-S, Ackermann C, Tóth I, Dierks P, Eberhard JM, Wroblewski R, et al. Down-regulation of CD73 on B cells of patients with viremic HIV correlates with B cell activation and disease progression. J Leukoc Biol. 2017;101:1263–71.
Kaku H, Cheng KF, Al-Abed Y, Rothstein TL. A novel mechanism of B cell-mediated immune suppression through CD73 expression and adenosine production. J Immunol Balt Md. 2014;193:5904–13.
Conter LJ, Song E, Shlomchik MJ, Tomayko MM. CD73 expression is dynamically regulated in the germinal center and bone marrow plasma cells are diminished in its absence. PloS ONE. 2014;9:e92009.
Bowser JL, Blackburn MR, Shipley GL, Molina JG, Dunner K, Broaddus RR. Loss of CD73-mediated actin polymerization promotes endometrial tumor progression. J Clin Investig. 2016;126:220–38.
Ohtani H, Komeno T, Agatsuma Y, Kobayashi M, Noguchi M, Nakamura N. Follicular dendritic cell meshwork in angioimmunoblastic T-cell lymphoma is characterized by accumulation of CXCL13(+) cells. J Clin Exp Hematop JCEH. 2015;55:61–69.
The authors acknowledge grant funding in support of this work from the Leukemia & Lymphoma Society (LLS), the National Institutes of Health (P50 CA97274), and the Predolin Foundation.
Conflict of interest
For JRC research funding provided by NanoString and BMS/Celgene. For SMA, research funding provided by Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Trillium and Takeda. The remaining authors report nothing to disclose.
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Pritchett, J.C., Yang, ZZ., Kim, H.J. et al. High-dimensional and single-cell transcriptome analysis of the tumor microenvironment in angioimmunoblastic T cell lymphoma (AITL). Leukemia 36, 165–176 (2022). https://doi.org/10.1038/s41375-021-01321-2