Journal Article
. 2021 Oct; 6(20):.
doi: 10.1172/jci.insight.151035.

Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness

Daniel Hirschhorn 1 Allison Betof Warner 1 Rachana Maniyar 1 Andrew Chow 1 Levi Mb Mangarin 1 Adam D Cohen 1 Linda Hamadene 1 Gabrielle A Rizzuto 1 Sadna Budhu 1 Nathan Suek 1 Cailian Liu 1 Alan N Houghton 1 Taha Merghoub 1 Jedd D Wolchok 1 
Affiliations
  • PMID: 34676831
  •     86 References

Abstract

Only a subset of cancer patients responds to checkpoint blockade inhibition in the clinic. Strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) has shown efficacy in preclinical models, but GITR engagement is ineffective in controlling advanced, poorly immunogenic tumors, such as B16 melanoma, and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) depletes regulatory T cells (Tregs), expands tumor-specific effector T cells (Teffs) via homeostatic proliferation, and induces immunogenic cell death. GITR agonism has an inhibitory effect on Tregs and activates Teffs. We therefore hypothesized that CTX and GITR agonism would promote effective antitumor immunity. Here we show that the combination of CTX and GITR agonism controlled tumor growth in clinically relevant mouse models. Mechanistically, we show that the combination therapy caused tumor cell death, clonal expansion of highly active CD8+ T cells, and depletion of Tregs by activation-induced cell death. Control of tumor growth was associated with the presence of an expanded population of highly activated, tumor-infiltrating, oligoclonal CD8+ T cells that led to a diminished TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemoimmunotherapeutic approach that warrants further clinical investigation.

Keywords: Cancer immunotherapy; Immunology; Melanoma; Oncology; T cells.

Clonal replacement of tumor-specific T cells following PD-1 blockade.
Kathryn E Yost, Ansuman T Satpathy, +13 authors, Howard Y Chang.
Nat Med, 2019 Jul 31; 25(8). PMID: 31359002    Free PMC article.
Highly Cited.
Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias.
Renier J Brentjens, Isabelle Rivière, +24 authors, Michel Sadelain.
Blood, 2011 Aug 19; 118(18). PMID: 21849486    Free PMC article.
Highly Cited.
Deep Sequencing of T-cell Receptor DNA as a Biomarker of Clonally Expanded TILs in Breast Cancer after Immunotherapy.
David B Page, Jianda Yuan, +22 authors, Heather L McArthur.
Cancer Immunol Res, 2016 Sep 03; 4(10). PMID: 27587469    Free PMC article.
Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials.
Seongseok Yun, Nicole D Vincelette, +2 authors, Ivo Abraham.
Cancer Med, 2016 May 12; 5(7). PMID: 27167347    Free PMC article.
Systematic Review.
Preexisting Levels of CD4 T Cells Expressing PD-1 Are Related to Overall Survival in Prostate Cancer Patients Treated with Ipilimumab.
Serena S Kwek, Jera Lewis, +7 authors, Lawrence Fong.
Cancer Immunol Res, 2015 May 15; 3(9). PMID: 25968455    Free PMC article.
Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
Mark A Socinski, Robert M Jotte, +18 authors, IMpower150 Study Group.
N Engl J Med, 2018 Jun 05; 378(24). PMID: 29863955
Highly Cited.
Cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks.
D Anderson, J B Bishop, +2 authors, P B Selby.
Mutat Res, 1995 Aug 01; 330(1-2). PMID: 7623863
Review.
Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells.
R J North.
J Exp Med, 1982 Apr 01; 155(4). PMID: 6460831    Free PMC article.
Highly Cited.
KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity.
Dietmar Herndler-Brandstetter, Harumichi Ishigame, +13 authors, Richard A Flavell.
Immunity, 2018 Apr 08; 48(4). PMID: 29625895    Free PMC article.
Highly Cited.
Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.
Peter Schmid, Sylvia Adams, +16 authors, IMpassion130 Trial Investigators.
N Engl J Med, 2018 Oct 23; 379(22). PMID: 30345906
Highly Cited.
A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection.
Haina Shin, Shawn D Blackburn, +4 authors, E John Wherry.
Immunity, 2009 Aug 12; 31(2). PMID: 19664943    Free PMC article.
Highly Cited.
Community detection algorithms: a comparative analysis.
Andrea Lancichinetti, Santo Fortunato.
Phys Rev E Stat Nonlin Soft Matter Phys, 2010 Apr 07; 80(5 Pt 2). PMID: 20365053
Highly Cited.
Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective.
Dung T Le, Elizabeth M Jaffee.
Cancer Res, 2012 Jul 05; 72(14). PMID: 22761338    Free PMC article.
Highly Cited. Review.
Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma.
Hiroyuki Inoue, Jae-Hyun Park, +16 authors, Yusuke Nakamura.
Oncoimmunology, 2016 Oct 21; 5(9). PMID: 27757299    Free PMC article.
High Levels of Eomes Promote Exhaustion of Anti-tumor CD8+ T Cells.
Jing Li, Yi He, +2 authors, Chen Dong.
Front Immunol, 2019 Jan 09; 9. PMID: 30619337    Free PMC article.
Combination Controversies: Checkpoint Inhibition Alone or in Combination for the Treatment of Melanoma?
Allison Betof Warner, Michael A Postow.
Oncology (Williston Park), 2018 May 31; 32(5). PMID: 29847853
Review.
Medium dose intermittent cyclophosphamide induces immunogenic cell death and cancer cell autonomous type I interferon production in glioma models.
Bin Du, David J Waxman.
Cancer Lett, 2019 Nov 26; 470. PMID: 31765733    Free PMC article.
Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs.
Fernando Cruz-Guilloty, Matthew E Pipkin, +5 authors, Anjana Rao.
J Exp Med, 2009 Jan 14; 206(1). PMID: 19139168    Free PMC article.
Highly Cited.
Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation.
J Adam Best, David A Blair, +6 authors, Immunological Genome Project Consortium.
Nat Immunol, 2013 Feb 12; 14(4). PMID: 23396170    Free PMC article.
Highly Cited.
Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells.
Kuibeom Ko, Sayuri Yamazaki, +7 authors, Shimon Sakaguchi.
J Exp Med, 2005 Sep 28; 202(7). PMID: 16186187    Free PMC article.
Highly Cited.
Homeostatic T cell proliferation: how far can T cells be activated to self-ligands?
C D Surh, J Sprent.
J Exp Med, 2000 Aug 22; 192(4). PMID: 10952731    Free PMC article.
Review.
Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer.
G Schiavoni, F Mattei, +4 authors, E Proietti.
Blood, 2000 Mar 09; 95(6). PMID: 10706870
CTLA4 blockade broadens the peripheral T-cell receptor repertoire.
Lidia Robert, Jennifer Tsoi, +11 authors, Antoni Ribas.
Clin Cancer Res, 2014 Mar 04; 20(9). PMID: 24583799    Free PMC article.
Highly Cited.
Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.
Luis Paz-Ares, Alexander Luft, +20 authors, KEYNOTE-407 Investigators.
N Engl J Med, 2018 Oct 04; 379(21). PMID: 30280635
Highly Cited.
Role of GITR in activation response of T lymphocytes.
Simona Ronchetti, Giuseppe Nocentini, Carlo Riccardi, Pier Paolo Pandolfi.
Blood, 2002 Jun 19; 100(1). PMID: 12070049
Regulatory T cells in cancer immunotherapy.
Atsushi Tanaka, Shimon Sakaguchi.
Cell Res, 2016 Dec 21; 27(1). PMID: 27995907    Free PMC article.
Highly Cited. Review.
Are Regulatory T Cells Defective in Type 1 Diabetes and Can We Fix Them?
Anabelle Visperas, Dario A A Vignali.
J Immunol, 2016 Nov 07; 197(10). PMID: 27815439    Free PMC article.
Review.
Glucocorticoid-induced tumour necrosis factor receptor-related protein: a key marker of functional regulatory T cells.
Simona Ronchetti, Erika Ricci, +4 authors, Carlo Riccardi.
J Immunol Res, 2015 May 12; 2015. PMID: 25961057    Free PMC article.
Review.
Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity.
Eiji Suzuki, Veena Kapoor, +2 authors, Steven M Albelda.
Clin Cancer Res, 2005 Sep 17; 11(18). PMID: 16166452
Highly Cited.
Validation of hysterectomy indications and the quality assurance process.
J C Gambone, J B Lench, +2 authors, J G Moore.
Obstet Gynecol, 1989 Jun 01; 73(6). PMID: 2726108
Clinical Application of Anti-CCR4 Monoclonal Antibody.
Ryuzo Ueda.
Oncology, 2015 Nov 10; 89 Suppl 1. PMID: 26550987
Review.
Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients.
Edward Cha, Mark Klinger, +4 authors, Lawrence Fong.
Sci Transl Med, 2014 May 30; 6(238). PMID: 24871131    Free PMC article.
Highly Cited.
Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis.
Xin Yu, Lei Zhang, +2 authors, Wenjun Ouyang.
J Leukoc Biol, 2020 Apr 10; 107(6). PMID: 32272497    Free PMC article.
Review.
Rational design of anti-GITR-based combination immunotherapy.
Roberta Zappasodi, Cynthia Sirard, +16 authors, Taha Merghoub.
Nat Med, 2019 May 01; 25(5). PMID: 31036879    Free PMC article.
Highly Cited.
PD-1 blockade induces responses by inhibiting adaptive immune resistance.
Paul C Tumeh, Christina L Harview, +23 authors, Antoni Ribas.
Nature, 2014 Nov 28; 515(7528). PMID: 25428505    Free PMC article.
Highly Cited.
Cyclophosphamide decreases the number, percentage and the function of CD25+ CD4+ regulatory T cells, which suppress induction of contact hypersensitivity.
Yuko Ikezawa, Masatoshi Nakazawa, +3 authors, Zenro Ikezawa.
J Dermatol Sci, 2005 May 19; 39(2). PMID: 15899580
Comparative transcriptome analysis reveals distinct genetic modules associated with Helios expression in intratumoral regulatory T cells.
Kathleen Yates, Kevin Bi, +2 authors, Hye-Jung Kim.
Proc Natl Acad Sci U S A, 2018 Feb 15; 115(9). PMID: 29440380    Free PMC article.
Inhibiting the CD8+ T cell infiltration in the tumor microenvironment after radiotherapy is an important mechanism of radioresistance.
Hai-Yan Chen, Lei Xu, +3 authors, Yong-Rui Bai.
Sci Rep, 2018 Aug 11; 8(1). PMID: 30093664    Free PMC article.
Immune-potentiating effects of the chemotherapeutic drug cyclophosphamide.
Sven Brode, Anne Cooke.
Crit Rev Immunol, 2008 Jun 11; 28(2). PMID: 18540827
Review.
Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy.
Jing Lu, Linda Lee-Gabel, +2 authors, Scott A Soefje.
J Oncol Pharm Pract, 2014 Jun 12; 21(6). PMID: 24917416
Review.
Regulatory T cells in cancer immunosuppression - implications for anticancer therapy.
Yosuke Togashi, Kohei Shitara, Hiroyoshi Nishikawa.
Nat Rev Clin Oncol, 2019 Feb 02; 16(6). PMID: 30705439
Highly Cited. Review.
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
Nicholas McGranahan, Andrew J S Furness, +33 authors, Charles Swanton.
Science, 2016 Mar 05; 351(6280). PMID: 26940869    Free PMC article.
Highly Cited.
Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.
Alexandra Snyder, Tavi Nathanson, +18 authors, Dean F Bajorin.
PLoS Med, 2017 May 30; 14(5). PMID: 28552987    Free PMC article.
Highly Cited.
Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted.
Young H Kim, Su M Shin, +7 authors, Byoung S Kwon.
J Immunol, 2015 Oct 02; 195(10). PMID: 26423152
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model.
Katherine A Waugh, Sonia M Leach, +3 authors, Jill E Slansky.
J Immunol, 2016 Jul 03; 197(4). PMID: 27371726    Free PMC article.
Ushering in Integrated T Cell Repertoire Profiling in Cancer.
Ning Jiang, Alexandra A Schonnesen, Ke-Yue Ma.
Trends Cancer, 2019 Feb 14; 5(2). PMID: 30755308    Free PMC article.
Review.
BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes.
Zachary A Cooper, Dennie T Frederick, +7 authors, Jennifer A Wargo.
Oncoimmunology, 2013 Nov 20; 2(10). PMID: 24251082    Free PMC article.
OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis.
Daniel Hirschhorn-Cymerman, Gabrielle A Rizzuto, +6 authors, Alan N Houghton.
J Exp Med, 2009 May 06; 206(5). PMID: 19414558    Free PMC article.
Molecular T-Cell Repertoire Analysis as Source of Prognostic and Predictive Biomarkers for Checkpoint Blockade Immunotherapy.
Ilenia Aversa, Donatella Malanga, Giuseppe Fiume, Camillo Palmieri.
Int J Mol Sci, 2020 Apr 03; 21(7). PMID: 32235561    Free PMC article.
Review.
Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity.
Teresa Ramirez-Montagut, Andrew Chow, +7 authors, Marcel R M van den Brink.
J Immunol, 2006 May 20; 176(11). PMID: 16709800
Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties.
Rachel L Rutishauser, Gislâine A Martins, +6 authors, Susan M Kaech.
Immunity, 2009 Aug 12; 31(2). PMID: 19664941    Free PMC article.
Highly Cited.
The sensitivity of lymphocytes to ionising radiation.
O A TROWELL.
J Pathol Bacteriol, 1952 Oct 01; 64(4). PMID: 13000583
Highly Cited.
GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability.
David A Schaer, Sadna Budhu, +8 authors, Jedd D Wolchok.
Cancer Immunol Res, 2014 Jan 15; 1(5). PMID: 24416730    Free PMC article.
Highly Cited.
Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction.
Qizhi Tang, Jason Y Adams, +6 authors, Jeffrey A Bluestone.
Immunity, 2008 May 13; 28(5). PMID: 18468463    Free PMC article.
Highly Cited.
The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
Highly Cited. Review.
CD8+ T cell states in human cancer: insights from single-cell analysis.
Anne M van der Leun, Daniela S Thommen, Ton N Schumacher.
Nat Rev Cancer, 2020 Feb 07; 20(4). PMID: 32024970    Free PMC article.
Review.
Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing.
Xinyi Guo, Yuanyuan Zhang, +16 authors, Zemin Zhang.
Nat Med, 2018 Jun 27; 24(7). PMID: 29942094
Highly Cited.
GITR triggering induces expansion of both effector and regulatory CD4+ T cells in vivo.
Ronald W van Olffen, Nathalie Koning, +6 authors, Martijn A Nolte.
J Immunol, 2009 Jun 06; 182(12). PMID: 19494272
Immune repertoire: A potential biomarker and therapeutic for hepatocellular carcinoma.
Yingxin Han, Hongmei Li, Yanfang Guan, Jian Huang.
Cancer Lett, 2015 Jul 19; 379(2). PMID: 26188280
Review.
Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.
Willem W Overwijk, Marc R Theoret, +15 authors, Nicholas P Restifo.
J Exp Med, 2003 Aug 20; 198(4). PMID: 12925674    Free PMC article.
Highly Cited.
IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus.
Saskia Hemmers, Michail Schizas, +5 authors, Alexander Y Rudensky.
J Exp Med, 2019 Aug 23; 216(11). PMID: 31434685    Free PMC article.
Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.
Jun Shimizu, Sayuri Yamazaki, +2 authors, Shimon Sakaguchi.
Nat Immunol, 2002 Jan 29; 3(2). PMID: 11812990
Highly Cited.
Treatment-Induced Tumor Cell Apoptosis and Secondary Necrosis Drive Tumor Progression in the Residual Tumor Microenvironment through MerTK and IDO1.
Thomas A Werfel, David L Elion, +9 authors, Rebecca S Cook.
Cancer Res, 2018 Nov 11; 79(1). PMID: 30413412
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.
Leena Gandhi, Delvys Rodríguez-Abreu, +27 authors, KEYNOTE-189 Investigators.
N Engl J Med, 2018 Apr 17; 378(22). PMID: 29658856
Highly Cited.
Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis.
Bin Shang, Yao Liu, Shu-juan Jiang, Yi Liu.
Sci Rep, 2015 Oct 16; 5. PMID: 26462617    Free PMC article.
Highly Cited. Systematic Review.
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
Sergio A Quezada, Karl S Peggs, Michael A Curran, James P Allison.
J Clin Invest, 2006 Jun 17; 116(7). PMID: 16778987    Free PMC article.
Highly Cited.
A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.
Chris Hunter, Raffaella Smith, +52 authors, Richard Wooster.
Cancer Res, 2006 Apr 19; 66(8). PMID: 16618716    Free PMC article.
Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics.
Marlon Stoeckius, Shiwei Zheng, +5 authors, Rahul Satija.
Genome Biol, 2018 Dec 21; 19(1). PMID: 30567574    Free PMC article.
Highly Cited.
Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance.
Whijae Roh, Pei-Ling Chen, +37 authors, P Andrew Futreal.
Sci Transl Med, 2017 Mar 03; 9(379). PMID: 28251903    Free PMC article.
Highly Cited.
Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
François Ghiringhelli, Cedric Menard, +7 authors, Bruno Chauffert.
Cancer Immunol Immunother, 2006 Sep 09; 56(5). PMID: 16960692
Highly Cited.
Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration.
Laura Bracci, Federica Moschella, +8 authors, Enrico Proietti.
Clin Cancer Res, 2007 Jan 27; 13(2 Pt 1). PMID: 17255288
CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative.
François Ghiringhelli, Nicolas Larmonier, +7 authors, François Martin.
Eur J Immunol, 2004 Feb 10; 34(2). PMID: 14768038
Highly Cited.
Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation.
Adam D Cohen, David A Schaer, +10 authors, Jedd D Wolchok.
PLoS One, 2010 May 11; 5(5). PMID: 20454651    Free PMC article.
Highly Cited.
T-Regulatory Cells In Tumor Progression And Therapy.
Amit Verma, Rohit Mathur, +3 authors, Bilikere S Dwarakanath.
Cancer Manag Res, 2020 Jan 11; 11. PMID: 31920383    Free PMC article.
Review.
Clonal expansion of antitumor T cells in breast cancer correlates with response to neoadjuvant chemotherapy.
Jae-Hyun Park, Miran Jang, +10 authors, Yusuke Nakamura.
Int J Oncol, 2016 Jun 10; 49(2). PMID: 27278091    Free PMC article.
High-throughput sequencing of the T-cell receptor repertoire: pitfalls and opportunities.
James M Heather, Mazlina Ismail, Theres Oakes, Benny Chain.
Brief Bioinform, 2017 Jan 13; 19(4). PMID: 28077404    Free PMC article.
Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy.
David A Schaer, Daniel Hirschhorn-Cymerman, Jedd D Wolchok.
J Immunother Cancer, 2014 May 24; 2. PMID: 24855562    Free PMC article.
Review.
Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment.
Daniel P Cahill, Kymberly K Levine, +9 authors, David N Louis.
Clin Cancer Res, 2007 Apr 04; 13(7). PMID: 17404084    Free PMC article.
Highly Cited.
T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection.
Marcus Buggert, Johanna Tauriainen, +10 authors, Annika C Karlsson.
PLoS Pathog, 2014 Jul 18; 10(7). PMID: 25032686    Free PMC article.
Highly Cited.
The Diagnostic, Prognostic, and Therapeutic Potential of Adaptive Immune Receptor Repertoire Profiling in Cancer.
Lindsay G Cowell.
Cancer Res, 2020 Jan 01; 80(4). PMID: 31888887
Review.
Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells.
Anna K Nowak, Richard A Lake, +5 authors, Bruce W S Robinson.
J Immunol, 2003 May 08; 170(10). PMID: 12734333
Highly Cited.
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Meromit Singer, Chao Wang, +16 authors, Ana C Anderson.
Cell, 2016 Sep 10; 166(6). PMID: 27610572    Free PMC article.
Highly Cited.
T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response.
Benjamin A Kansy, Gulidanna Shayan, +8 authors, Robert L Ferris.
Oncoimmunology, 2018 Nov 01; 7(11). PMID: 30377562    Free PMC article.
Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells.
Mary Jo Turk, José A Guevara-Patiño, +3 authors, Alan N Houghton.
J Exp Med, 2004 Sep 24; 200(6). PMID: 15381730    Free PMC article.
Highly Cited.
Characterization of the T cell repertoire by deep T cell receptor sequencing in tissues and blood from patients with advanced colorectal cancer.
Kenji Tamura, Shoichi Hazama, +8 authors, Kazuma Kiyotani.
Oncol Lett, 2016 Jun 11; 11(6). PMID: 27284367    Free PMC article.