摘要
目的:探讨PAXT基因突变对肿瘤免疫的影响。 背景:PAX5功能丧失在PAX5突变肿瘤中起着关键作用。 目的:PAX5单倍不全促进肿瘤发生与免疫逃逸有关,但目前尚无关于PAX5突变诱导肿瘤免疫逃逸的机制的报道。 方法:采用基因编辑技术构建PAX5单倍缺失A20细胞系,构建A20同种异体移植瘤模型,并评价PAX5单倍缺失对肿瘤微环境(TME)中T细胞及趋化因子的影响。 结果:PAX5单倍体缺失克隆的TME中CD3+ CD4+ T细胞百分比和CD3+ CD8+ T细胞百分比均较野生型显著降低。PAX5的TME中存在多种趋化因子,如Ccl2、Ccl4、Cxcl9和Cxcl10。 结论:我们的研究表明PAX5单倍体功能不全通过降低趋化因子诱导TME中T细胞浸润降低。
关键词: Pax5,单倍体功能不全,非t细胞炎性肿瘤,淋巴瘤,免疫治疗,细胞因子。
[1]
Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: A master regulator of B cell development and leukemogenesis. Adv Immunol 2011; 111: 179-206.
[http://dx.doi.org/10.1016/B978-0-12-385991-4.00005-2] [PMID: 21970955]
[http://dx.doi.org/10.1016/B978-0-12-385991-4.00005-2] [PMID: 21970955]
[2]
Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446(7137): 758-64.
[http://dx.doi.org/10.1038/nature05690] [PMID: 17344859]
[http://dx.doi.org/10.1038/nature05690] [PMID: 17344859]
[3]
Iacobucci I, Lonetti A, Paoloni F, et al. The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome. A report on behalf of the GIMEMA acute leukemia working party. Haematologica 2010; 95(10): 1683-90.
[http://dx.doi.org/10.3324/haematol.2009.020792] [PMID: 20534699]
[http://dx.doi.org/10.3324/haematol.2009.020792] [PMID: 20534699]
[4]
Kim M, Choi JE, She CJ, et al. PAX5 deletion is common and concurrently occurs with CDKN2A deletion in B-lineage acute lymphoblastic leukemia. Blood Cells Mol Dis 2011; 47(1): 62-6.
[http://dx.doi.org/10.1016/j.bcmd.2011.04.003] [PMID: 21549623]
[http://dx.doi.org/10.1016/j.bcmd.2011.04.003] [PMID: 21549623]
[5]
Liso A, Capello D, Marafioti T, et al. Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma. Blood 2006; 108(3): 1013-20.
[http://dx.doi.org/10.1182/blood-2005-10-3949] [PMID: 16614247]
[http://dx.doi.org/10.1182/blood-2005-10-3949] [PMID: 16614247]
[6]
Gaidano G, Pasqualucci L, Capello D, et al. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma. Blood 2003; 102(5): 1833-41.
[http://dx.doi.org/10.1182/blood-2002-11-3606] [PMID: 12714522]
[http://dx.doi.org/10.1182/blood-2002-11-3606] [PMID: 12714522]
[7]
Montesinos-Rongen M, Van Roost D, Schaller C, Wiestler OD, Deckert M. Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation. Blood 2004; 103(5): 1869-75.
[http://dx.doi.org/10.1182/blood-2003-05-1465] [PMID: 14592832]
[http://dx.doi.org/10.1182/blood-2003-05-1465] [PMID: 14592832]
[8]
Teo AE, Chen Z, Miranda RN, McDonnell T, Medeiros LJ, McCarty N. Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1. Leukemia 2016; 30(3): 580-93.
[http://dx.doi.org/10.1038/leu.2015.140] [PMID: 26073757]
[http://dx.doi.org/10.1038/leu.2015.140] [PMID: 26073757]
[9]
Liu XM, Zhang L, Ruan M, et al. Significance of PAX5 deletion in childhood B-lineage acute lymphoblastic leukemia without reproducible chromosomal abnormalities. Zhongguo Dang Dai Er Ke Za Zhi 2016; 18(4): 287-91.
[PMID: 27097569]
[PMID: 27097569]
[10]
Gu Z, Churchman ML, Roberts KG, et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat Genet 2019; 51(2): 296-307.
[http://dx.doi.org/10.1038/s41588-018-0315-5] [PMID: 30643249]
[http://dx.doi.org/10.1038/s41588-018-0315-5] [PMID: 30643249]
[11]
Kawamata N, Pennella MA, Woo JL, Berk AJ, Koeffler HP. Dominant-negative mechanism of leukemogenic PAX5 fusions. Oncogene 2012; 31(8): 966-77.
[http://dx.doi.org/10.1038/onc.2011.291] [PMID: 21765475]
[http://dx.doi.org/10.1038/onc.2011.291] [PMID: 21765475]
[12]
Dang J, Wei L, de Ridder J, et al. PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia. Blood 2015; 125(23): 3609-17.
[http://dx.doi.org/10.1182/blood-2015-02-626127] [PMID: 25855603]
[http://dx.doi.org/10.1182/blood-2015-02-626127] [PMID: 25855603]
[13]
Heltemes-Harris LM, Willette MJL, Ramsey LB, et al. Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia. J Exp Med 2011; 208(6): 1135-49.
[http://dx.doi.org/10.1084/jem.20101947] [PMID: 21606506]
[http://dx.doi.org/10.1084/jem.20101947] [PMID: 21606506]
[14]
Martín-Lorenzo A, Auer F, Chan LN, et al. Loss of Pax5 exploits Sca1-BCR-ABLp190 Susceptibility to Confer the metabolic shift essential for pB-ALL. Cancer Res 2018; 78(10): 2669-79.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-3262] [PMID: 29490943]
[http://dx.doi.org/10.1158/0008-5472.CAN-17-3262] [PMID: 29490943]
[15]
Trujillo JA, Sweis RF, Bao R, Luke JJ. T cell-inflamed versus Non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection. Cancer Immunol Res 2018; 6(9): 990-1000.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0277] [PMID: 30181337]
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0277] [PMID: 30181337]
[16]
Gu J, Li T, Zhao L, et al. Identification of significant pathways induced by PAX5 haploinsufficiency based on protein-protein interaction networks and cluster analysis in raji cell line. BioMed Res Int 2017; 2017: 5326370.
[http://dx.doi.org/10.1155/2017/5326370] [PMID: 28316978]
[http://dx.doi.org/10.1155/2017/5326370] [PMID: 28316978]
[17]
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646-74.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[18]
Spranger S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int Immunol 2016; 28(8): 383-91.
[http://dx.doi.org/10.1093/intimm/dxw014] [PMID: 26989092]
[http://dx.doi.org/10.1093/intimm/dxw014] [PMID: 26989092]
[19]
Gajewski TF. The next hurdle in cancer immunotherapy: overcoming the non-t-cell-inflamed tumor microenvironment. Semin Oncol 2015; 42(4): 663-71.
[http://dx.doi.org/10.1053/j.seminoncol.2015.05.011] [PMID: 26320069]
[http://dx.doi.org/10.1053/j.seminoncol.2015.05.011] [PMID: 26320069]
[20]
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371(23): 2189-99.
[http://dx.doi.org/10.1056/NEJMoa1406498] [PMID: 25409260]
[http://dx.doi.org/10.1056/NEJMoa1406498] [PMID: 25409260]
[21]
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 2016; 8(328): 328rv4.
[http://dx.doi.org/10.1126/scitranslmed.aad7118] [PMID: 26936508]
[http://dx.doi.org/10.1126/scitranslmed.aad7118] [PMID: 26936508]
[22]
Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348(3): 203-13.
[http://dx.doi.org/10.1056/NEJMoa020177] [PMID: 12529460]
[http://dx.doi.org/10.1056/NEJMoa020177] [PMID: 12529460]
[23]
Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 2005; 102(51): 18538-43.
[http://dx.doi.org/10.1073/pnas.0509182102] [PMID: 16344461]
[http://dx.doi.org/10.1073/pnas.0509182102] [PMID: 16344461]
[24]
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313(5795): 1960-4.
[http://dx.doi.org/10.1126/science.1129139] [PMID: 17008531]
[http://dx.doi.org/10.1126/science.1129139] [PMID: 17008531]
[25]
Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 2017; 17(9): 559-72.
[http://dx.doi.org/10.1038/nri.2017.49] [PMID: 28555670]
[http://dx.doi.org/10.1038/nri.2017.49] [PMID: 28555670]
[26]
Amati AL, Zakrzewicz A, Siebers R, et al. Chemokines (CCL3, CCL4, and CCL5) inhibit ATP-Induced release of IL-1β by monocytic cells. Mediators Inflamm 2017; 2017: 1434872.
[http://dx.doi.org/10.1155/2017/1434872] [PMID: 28757683]
[http://dx.doi.org/10.1155/2017/1434872] [PMID: 28757683]
[27]
De la Fuente López M, Landskron G, Parada D, et al. The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour Biol 2018; 40(11): 1010428318810059.
[http://dx.doi.org/10.1177/1010428318810059] [PMID: 30419802]
[http://dx.doi.org/10.1177/1010428318810059] [PMID: 30419802]
[28]
Brown CE, Vishwanath RP, Aguilar B, et al. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J Immunol 2007; 179(5): 3332-41.
[http://dx.doi.org/10.4049/jimmunol.179.5.3332] [PMID: 17709550]
[http://dx.doi.org/10.4049/jimmunol.179.5.3332] [PMID: 17709550]
[29]
Allen F, Bobanga ID, Rauhe P, et al. CCL3 augments tumor rejection and enhances CD8+ T cell infiltration through NK and CD103+ dendritic cell recruitment via IFNγ. OncoImmunology 2017; 7(3): e1393598.
[http://dx.doi.org/10.1080/2162402X.2017.1393598] [PMID: 29399390]
[http://dx.doi.org/10.1080/2162402X.2017.1393598] [PMID: 29399390]
[30]
Sektioglu IM, Carretero R, Bulbuc N, et al. Basophils promote tumor rejection via chemotaxis and infiltration of CD8+ T Cells. Cancer Res 2017; 77(2): 291-302.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0993] [PMID: 27879269]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0993] [PMID: 27879269]
[31]
Liu JY, Li F, Wang LP, et al. CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer 2015; 113(5): 747-55.
[http://dx.doi.org/10.1038/bjc.2015.290] [PMID: 26284335]
[http://dx.doi.org/10.1038/bjc.2015.290] [PMID: 26284335]
[32]
Wang X, Lang M, Zhao T, et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+treg cells in pancreatic ductal adenocarcinoma. Oncogene 2017; 36(21): 3048-58.
[http://dx.doi.org/10.1038/onc.2016.458] [PMID: 27991933]
[http://dx.doi.org/10.1038/onc.2016.458] [PMID: 27991933]