Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

Humans Female Ovarian Neoplasms / immunology Neoadjuvant Therapy / methods Antibodies, Monoclonal, Humanized / therapeutic use CD8-Positive T-Lymphocytes / immunology Vascular Endothelial Growth Factor Receptor-2 / genetics Forkhead Transcription Factors / metabolism Programmed Cell Death 1 Receptor / metabolism Tumor Microenvironment / immunology Antineoplastic Combined Chemotherapy Protocols / therapeutic use Neoplasm Grading B7-H1 Antigen / metabolism Immunotherapy / methods

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
16 Jul 2024

Historique:

received: 25 02 2023

accepted: 18 03 2024

medline: 17 7 2024

pubmed: 17 7 2024

entrez: 16 7 2024

Statut: epublish

Résumé

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8

Identifiants

DOI: 10.1038/s41467-024-47000-5 PMID: 39013886

pubmed: 39013886

doi: 10.1038/s41467-024-47000-5

pii: 10.1038/s41467-024-47000-5

doi:

Substances chimiques

Antibodies, Monoclonal, Humanized 0

pembrolizumab DPT0O3T46P

Vascular Endothelial Growth Factor Receptor-2 EC 2.7.10.1

FOXP3 protein, human 0

Forkhead Transcription Factors 0

Programmed Cell Death 1 Receptor 0

KDR protein, human EC 2.7.10.1

PDCD1 protein, human 0

B7-H1 Antigen 0

Types de publication

Journal Article Clinical Trial, Phase II Randomized Controlled Trial

Langues

eng

Sous-ensembles de citation

Pagination

5932

Subventions

Organisme : Fondation ARC pour la Recherche sur le Cancer (ARC Foundation for Cancer Research)

ID : PGA1 RC20170205307

Informations de copyright

Références

Zhang, Y. et al. Global patterns and trends in ovarian cancer incidence: age, period and birth cohort analysis. BMC Cancer 19, 984 (2019).

pubmed: 31640608 pmcid: 6806513 doi: 10.1186/s12885-019-6139-6

Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

pubmed: 12529460 doi: 10.1056/NEJMoa020177

Matulonis, U. A. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann. Oncol. 30, 1080–1087 (2019).

pubmed: 31046082 doi: 10.1093/annonc/mdz135

Mesnage, S. J. L. et al. Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC). Ann. Oncol. 28, 651–657 (2017).

pubmed: 27864219 doi: 10.1093/annonc/mdw625

Leary, A. et al. Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer. Cancer Immunol. Immunother. 70, 519–531 (2021).

pubmed: 32852603 doi: 10.1007/s00262-020-02670-0

Lo, C. S. et al. Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clin. Cancer Res. 23, 925–934 (2017).

pubmed: 27601594 doi: 10.1158/1078-0432.CCR-16-1433

Böhm, S. et al. Neoadjuvant chemotherapy modulates the immune microenvironment in metastases of tubo-ovarian high-grade serous carcinoma. Clin. Cancer Res. 22, 3025–3036 (2016).

pubmed: 27306793 doi: 10.1158/1078-0432.CCR-15-2657

Hao, D. et al. Immunogenomic analyses of advanced serous ovarian cancer reveal immune score is a strong prognostic factor and an indicator of chemosensitivity. Clin. Cancer Res. 24, 3560–3571 (2018).

pubmed: 29661778 doi: 10.1158/1078-0432.CCR-17-3862

Pujade-Lauraine, E. et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 22, 1034–1046 (2021).

pubmed: 34143970 doi: 10.1016/S1470-2045(21)00216-3

Monk, B. J. et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial. Lancet Oncol. 22, 1275–1289 (2021).

pubmed: 34363762 doi: 10.1016/S1470-2045(21)00342-9

Moore, K. N. et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J. Clin. Oncol. 39, 1842–1855 (2021).

pubmed: 33891472 pmcid: 8189598 doi: 10.1200/JCO.21.00306

Le Saux, O. et al. Current advances in immunotherapy in ovarian cancer. Bull. Cancer https://doi.org/10.1016/j.bulcan.2019.11.015 (2020).

Landen, C. N. et al. Influence of genomic landscape on cancer immunotherapy for newly diagnosed ovarian cancer: biomarker analyses from the IMagyn050 randomized clinical trial. Clin. Cancer Res. 29, 1698–1707 (2023).

pubmed: 36595569 pmcid: 10150250 doi: 10.1158/1078-0432.CCR-22-2032

Kawamura, K., Komohara, Y., Takaishi, K., Katabuchi, H. & Takeya, M. Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors. Pathol. Int. 59, 300–305 (2009).

pubmed: 19432671 doi: 10.1111/j.1440-1827.2009.02369.x

Vankerckhoven, A. et al. Opposite macrophage polarization in different subsets of ovarian cancer: observation from a pilot study. Cells 9, 305 (2020).

pubmed: 32012728 pmcid: 7072171 doi: 10.3390/cells9020305

Tan, Q., Liu, H., Xu, J., Mo, Y. & Dai, F. Integrated analysis of tumor-associated macrophage infiltration and prognosis in ovarian cancer. Aging 13, 23210–23232 (2021).

pubmed: 34633990 pmcid: 8544311 doi: 10.18632/aging.203613

Zhao, H. et al. Single-cell analysis revealed that IL4I1 promoted ovarian cancer progression. J. Transl. Med. 19, 454 (2021).

pubmed: 34717685 pmcid: 8557560 doi: 10.1186/s12967-021-03123-7

Bamias, A. et al. Correlation of NK T-like CD3+CD56+ cells and CD4+CD25+(hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: Association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy. Gynecol. Oncol. 108, 421–427 (2008).

pubmed: 18036640 doi: 10.1016/j.ygyno.2007.10.018

Bamias, A., Pignata, S. & Pujade-Lauraine, E. Angiogenesis: a promising therapeutic target for ovarian cancer. Crit. Rev. Oncol. Hematol. 84, 314–326 (2012).

pubmed: 22575381 doi: 10.1016/j.critrevonc.2012.04.002

Chen, P.-L. et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov. 6, 827–837 (2016).

pubmed: 27301722 pmcid: 5082984 doi: 10.1158/2159-8290.CD-15-1545

Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).

pubmed: 25601652 pmcid: 4322048 doi: 10.1084/jem.20140559

Ray-Coquard, I. et al. Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial. Nat. Commun. https://doi.org/10.1038/s41467-024-46999-x (2024).

Becht, E. et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 17, 1–20 (2016).

Finotello, F. et al. Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data. Genome Med. 11, 1–20 (2019).

Gros, A. et al. Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes. J. Clin. Invest. 129, 4992–5004 (2019).

pubmed: 31609250 pmcid: 6819109 doi: 10.1172/JCI127967

Caushi, J. X. et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 596, 126–132 (2021).

pubmed: 34290408 pmcid: 8338555 doi: 10.1038/s41586-021-03752-4

Joly, F. et al. Efficacy and long-term safety with bevacizumab included in neoadjuvant and adjuvant therapies in patients with advanced ovarian cancer: results of the ANTHALYA trial. JCO 35, 5538 (2017).

doi: 10.1200/JCO.2017.35.15_suppl.5538

Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).

pubmed: 19934295 doi: 10.1158/1078-0432.CCR-09-1624

Hoos, A., Wolchok, J. D., Humphrey, R. W. & Hodi, F. S. CCR 20th anniversary commentary: immune-related response criteria-capturing clinical activity in immuno-oncology. Clin. Cancer Res. 21, 4989–4991 (2015).

pubmed: 26567357 doi: 10.1158/1078-0432.CCR-14-3128

Le Saux, O. et al. 260 Impact of BRCA & PD-L1 in EOC patients receiving standard 1st line therapy +/- Pembrolizumab: exploratory analyses from the NeoPembrOV Study (GINECO). Int. J. Gynecol. Cancer 31, A216 (2021).

Saha, S. et al. SMARCD1 negatively regulates myeloid differentiation of leukemic cells via epigenetic mechanisms. Blood Adv. 6, 3106–3113 (2022).

pubmed: 35078226 pmcid: 9131909 doi: 10.1182/bloodadvances.2021006235

Foy, J.-P. et al. Immunologically active phenotype by gene expression profiling is associated with clinical benefit from PD-1/PD-L1 inhibitors in real-world head and neck and lung cancer patients. Eur. J. Cancer 174, 287–298 (2022).

pubmed: 36038492 doi: 10.1016/j.ejca.2022.06.034

Mamer, S. B. et al. Discovery of high-affinity PDGF-VEGFR interactions: redefining RTK dynamics. Sci. Rep. 7, 16439 (2017).

pubmed: 29180757 pmcid: 5704011 doi: 10.1038/s41598-017-16610-z

Ovarian Tumor Tissue Analysis (OTTA) Consortium. et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. 3, e173290 (2017).

doi: 10.1001/jamaoncol.2017.3290

Salas-Benito, D. et al. The mutational load and a T-cell inflamed tumour phenotype identify ovarian cancer patients rendering tumour-reactive T cells from PD-1+ tumour-infiltrating lymphocytes. Br. J. Cancer 124, 1138–1149 (2021).

pubmed: 33402737 pmcid: 7961070 doi: 10.1038/s41416-020-01218-4

Inozume, T. et al. Selection of CD8+PD-1+ lymphocytes in fresh human melanomas enriches for tumor-reactive T cells. J. Immunother. 33, 956–964 (2010).

pubmed: 20948441 pmcid: 2980947 doi: 10.1097/CJI.0b013e3181fad2b0

Jing, W. et al. Adoptive cell therapy using PD-1+ myeloma-reactive T cells eliminates established myeloma in mice. J. Immunother. Cancer 5, 51 (2017).

pubmed: 28642819 pmcid: 5477110 doi: 10.1186/s40425-017-0256-z

Fernandez-Poma, S. M. et al. Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T-cell therapy. Cancer Res. 77, 3672–3684 (2017).

pubmed: 28522749 doi: 10.1158/0008-5472.CAN-17-0236

Gros, A. et al. PD-1 identifies the patient-specific CD8

pubmed: 24667641 pmcid: 4001555 doi: 10.1172/JCI73639

Vanguri, R. et al. Understanding the impact of chemotherapy on the immune landscape of high-grade serous ovarian cancer. Gynecol. Oncol. Rep. 39, 100926 (2022).

pubmed: 35146104 pmcid: 8801989 doi: 10.1016/j.gore.2022.100926

Li, K. et al. Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy. Cancer Cell https://doi.org/10.1016/j.ccell.2022.10.001 (2022).

Thommen, D. 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. 24, 994–1004 (2018).

pubmed: 29892065 pmcid: 6110381 doi: 10.1038/s41591-018-0057-z

Kumagai, S. et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat. Immunol. 21, 1346–1358 (2020).

pubmed: 32868929 doi: 10.1038/s41590-020-0769-3

Zamarin, D. et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study. J. Clin. Oncol. https://doi.org/10.1200/JCO.19.02059 (2020).

Leary, A. et al. 727P Phase Ib INEOV neoadjuvant trial of the anti-PDL1, durvalumab (D) +/- anti-CTLA4 tremelimumab (T) with platinum chemotherapy for patients (pts) with unresectable ovarian cancer (OC): a GINECO study. Ann. Oncol. 32, S731 (2021).

doi: 10.1016/j.annonc.2021.08.1170

Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).

pubmed: 30006565 pmcid: 6045647 doi: 10.1038/s41467-018-05072-0

Canale, F. P. et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells. Cancer Res. 78, 115–128 (2018).

pubmed: 29066514 doi: 10.1158/0008-5472.CAN-16-2684

Chow, A. et al. The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer. Immunity 56, 93–106.e6 (2023).

pubmed: 36574773 doi: 10.1016/j.immuni.2022.12.001

Toker, A. et al. Regulatory T cells in ovarian cancer are characterized by a highly activated phenotype distinct from that in melanoma. Clin. Cancer Res. 24, 5685–5696 (2018).

pubmed: 30065096 doi: 10.1158/1078-0432.CCR-18-0554

Laumont, C. M. et al. Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes coexpressing CD39, CD103, and PD-1 in ovarian cancer. Clin. Cancer Res. 27, 4089–4100 (2021).

pubmed: 33963000 doi: 10.1158/1078-0432.CCR-20-4394

Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

pubmed: 31942071 doi: 10.1038/s41586-019-1914-8

Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

pubmed: 31942075 pmcid: 8762581 doi: 10.1038/s41586-019-1922-8

Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

pubmed: 31942077 doi: 10.1038/s41586-019-1906-8

Siliņa, K. et al. Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Res. 78, 1308–1320 (2018).

pubmed: 29279354 doi: 10.1158/0008-5472.CAN-17-1987

Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14, 28–36 (2008).

pubmed: 18157142 doi: 10.1038/nm1699

Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).

pubmed: 24793239 pmcid: 4060245 doi: 10.1038/nm.3541

Li, Y. et al. Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models. PLoS ONE 17, e0268244 (2022).

pubmed: 35849586 pmcid: 9292077 doi: 10.1371/journal.pone.0268244

Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012).

pubmed: 23045683 pmcid: 3491458 doi: 10.1073/pnas.1215397109

Chinnasamy, D. et al. Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. Cancer Res. 73, 3371–3380 (2013).

pubmed: 23633494 pmcid: 3686092 doi: 10.1158/0008-5472.CAN-12-3913

Chinnasamy, D. et al. Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. J. Clin. Invest. 120, 3953–3968 (2010).

pubmed: 20978347 pmcid: 2964987 doi: 10.1172/JCI43490

Premalata, C. S., Umadevi, K., Shobha, K., Anurekha, M. & Krishnamoorthy, L. Expression of VEGF-A in epithelial ovarian cancer: correlation with morphologic types, grade and clinical stage. Gulf J. Oncol. 1, 49–54 (2016).

Gavalas, N. G. et al. Angiogenesis-related pathways in the pathogenesis of ovarian cancer. Int. J. Mol. Sci. 14, 15885–15909 (2013).

pubmed: 23903048 pmcid: 3759892 doi: 10.3390/ijms140815885

Guo, B.-Q. & Lu, W.-Q. The prognostic significance of high/positive expression of tissue VEGF in ovarian cancer. Oncotarget 9, 30552–30560 (2018).

pubmed: 30093968 pmcid: 6078137 doi: 10.18632/oncotarget.25702

Reckamp, K. L. et al. Phase II randomized study of ramucirumab and pembrolizumab versus standard of care in advanced non–small-cell lung cancer previously treated with immunotherapy—lung-MAP S1800A. J. Clin. Oncol. 40, 2295–2306 (2022).

pubmed: 35658002 pmcid: 9287284 doi: 10.1200/JCO.22.00912

Opzoomer, J. W. et al. Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression. Sci. Adv. 7, eabg9518 (2021).

pubmed: 34730997 pmcid: 8565907 doi: 10.1126/sciadv.abg9518

Wang, R. et al. Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression. Lung Cancer 74, 188–196 (2011).

pubmed: 21601305 doi: 10.1016/j.lungcan.2011.04.009

Dineen, S. P. et al. Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res. 68, 4340–4346 (2008).

pubmed: 18519694 doi: 10.1158/0008-5472.CAN-07-6705

Yang, Y. et al. The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages. Nat. Commun. 7, 11385 (2016).

pubmed: 27150562 pmcid: 4859070 doi: 10.1038/ncomms11385

Zhang, Q. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829–845.e20 (2019).

pubmed: 31675496 doi: 10.1016/j.cell.2019.10.003

Hornburg, M. et al. Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer. Cancer Cell 39, 928–944.e6 (2021).

pubmed: 33961783 doi: 10.1016/j.ccell.2021.04.004

Binnewies, M. et al. Targeting TREM2 on tumor-associated macrophages enhances immunotherapy. Cell Rep. 37, 109844 (2021).

pubmed: 34686340 doi: 10.1016/j.celrep.2021.109844

Molgora, M. et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 182, 886–900.e17 (2020).

pubmed: 32783918 pmcid: 7485282 doi: 10.1016/j.cell.2020.07.013

Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

pubmed: 23104886 doi: 10.1093/bioinformatics/bts635

Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).

pubmed: 28263959 pmcid: 5600148 doi: 10.1038/nmeth.4197

Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

pubmed: 25516281 pmcid: 4302049 doi: 10.1186/s13059-014-0550-8

Raouf, A. et al. Transcriptome analysis of the normal human mammary cell commitment and differentiation process. Cell Stem Cell 3, 109–118 (2008).

pubmed: 18593563 doi: 10.1016/j.stem.2008.05.018

Peart, M. J. et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 102, 3697–3702 (2005).

pubmed: 15738394 pmcid: 552783 doi: 10.1073/pnas.0500369102

Sturm, G. et al. Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology. Bioinformatics 35, i436–i445 (2019).

pubmed: 31510660 pmcid: 6612828 doi: 10.1093/bioinformatics/btz363

Groeneveld, C. S. et al. Tertiary lymphoid structures marker CXCL13 is associated with better survival for patients with advanced-stage bladder cancer treated with immunotherapy. Eur. J. Cancer 148, 181–189 (2021).

pubmed: 33743486 doi: 10.1016/j.ejca.2021.01.036

Madissoon, E. et al. scRNA-seq assessment of the human lung, spleen, and esophagus tissue stability after cold preservation. Genome Biol. 21, 1–16 (2020).

doi: 10.1186/s13059-019-1906-x

O’Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).

pubmed: 14707116 pmcid: 1887725 doi: 10.1084/jem.20031330

Andreani, V. et al. Cochaperone Mzb1 is a key effector of Blimp1 in plasma cell differentiation and β1-integrin function. Proc. Natl Acad. Sci. USA 115, E9630–E9639 (2018).

pubmed: 30257949 pmcid: 6187189 doi: 10.1073/pnas.1809739115

Becht, E. et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 17, 218 (2016).

pubmed: 27765066 pmcid: 5073889 doi: 10.1186/s13059-016-1070-5

DiSanto, J. P., Smith, D., de Bruin, D., Lacy, E. & Flomenberg, N. Transcriptional diversity at the duplicated human CD8 beta loci. Eur. J. Immunol. 23, 320–326 (1993).

pubmed: 8436166 doi: 10.1002/eji.1830230203

Tibshirani, R. Regression shrinkage and selection via the lasso. J. R. Stat. Soc. Ser. B (Methodol.) 58, 267–288 (1996).

doi: 10.1111/j.2517-6161.1996.tb02080.x