Journal Article
. 2019 Oct; 116(45):22699-22709.
doi: 10.1073/pnas.1821218116.

Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies

Spencer C Wei 1 Nana-Ama A S Anang 1 Roshan Sharma 2 Miles C Andrews 3 Alexandre Reuben 3 Jacob H Levine 2 Alexandria P Cogdill 1 James J Mancuso 1 Jennifer A Wargo 4 Dana Pe'er 2 James P Allison 5 
  • PMID: 31636208
  •     51 References
  •     92 citations


Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti-CTLA-4 and anti-PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti-CTLA-4 plus anti-PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti-PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti-PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.

Keywords: CTLA-4; PD-1; T cell; immune checkpoint blockade; mass cytometry.

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Cancers (Basel), 2021 Jun 03; 13(11). PMID: 34071888    Free PMC article.
Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment.
Shota Aoyama, Ryosuke Nakagawa, +3 authors, Adam William Mailloux.
J Immunother Cancer, 2021 Jun 18; 9(6). PMID: 34135102    Free PMC article.
Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients-Mechanism of Action and Future Concepts.
Kamila Wojas-Krawczyk, Paweł Krawczyk, Michał Gil, Maciej Strzemski.
Cancers (Basel), 2021 Jul 03; 13(11). PMID: 34200219    Free PMC article.
First-Line Treatment Options for PD-L1-Negative Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.
Ling Peng, Wen-Hua Liang, +5 authors, Yang Xia.
Front Oncol, 2021 Jul 13; 11. PMID: 34249693    Free PMC article.
Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy.
Elodie Lauret Marie Joseph, Amos Kirilovsky, +20 authors, Olivier Adotevi.
J Immunother Cancer, 2021 Jul 08; 9(7). PMID: 34230108    Free PMC article.
The knowns & unknowns of pulmonary toxicity following immune checkpoint inhibitor therapies: a narrative review.
Alistair R Miller, Renee Manser.
Transl Lung Cancer Res, 2021 Jul 24; 10(6). PMID: 34295675    Free PMC article.
Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model.
Falih M Gorgun, Steven G Widen, Douglas S Tyler, Ella W Englander.
Front Oncol, 2021 Jul 24; 11. PMID: 34295826    Free PMC article.
Analysis of immune subtypes across the epithelial-mesenchymal plasticity spectrum.
Priyanka Chakraborty, Emily L Chen, +3 authors, Jason A Somarelli.
Comput Struct Biotechnol J, 2021 Jul 27; 19. PMID: 34306571    Free PMC article.
Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of Combination Immunotherapy.
Sonia Iyer, Shuang Zhang, +20 authors, Robert A Weinberg.
Cancer Discov, 2020 Nov 08; 11(2). PMID: 33158843    Free PMC article.
Combining Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach.
Chang-Gon Kim, Yun-Beom Sang, Ji-Hyun Lee, Hong-Jae Chon.
Int J Mol Sci, 2021 Aug 08; 22(15). PMID: 34360800    Free PMC article.
Virus-Like Particle-Drug Conjugates Induce Protective, Long-lasting Adaptive Antitumor Immunity in the Absence of Specifically Targeted Tumor Antigens.
Rhonda C Kines, Cynthia D Thompson, +4 authors, John T Schiller.
Cancer Immunol Res, 2021 Apr 16; 9(6). PMID: 33853825    Free PMC article.
Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies.
Shamin Li, Yannick Simoni, +10 authors, Evan W Newell.
Proc Natl Acad Sci U S A, 2021 Jul 22; 118(30). PMID: 34285073    Free PMC article.
Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells.
Murat Tekguc, James Badger Wing, +2 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2021 Jul 25; 118(30). PMID: 34301886    Free PMC article.
Re-Evaluating the Effects of Obesity on Cancer Immunotherapy Outcomes in Renal Cancer: What Do We Really Know?
Kristine I Farag, Amani Makkouk, Lyse A Norian.
Front Immunol, 2021 Aug 24; 12. PMID: 34421889    Free PMC article.
The cross talk between gastric cancer stem cells and the immune microenvironment: a tumor-promoting factor.
Jared Becerril-Rico, Eduardo Alvarado-Ortiz, +2 authors, Elizabeth Ortiz-Sánchez.
Stem Cell Res Ther, 2021 Sep 11; 12(1). PMID: 34503571    Free PMC article.
Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance.
Christiana M Neophytou, Ioannis P Trougakos, Nuray Erin, Panagiotis Papageorgis.
Cancers (Basel), 2021 Sep 11; 13(17). PMID: 34503172    Free PMC article.
New approaches to first-line treatment of advanced renal cell carcinoma.
Daniel J George, Chung-Han Lee, Daniel Heng.
Ther Adv Med Oncol, 2021 Sep 17; 13. PMID: 34527080    Free PMC article.
An Indirect Comparison Between Nivolumab + Ipilimumab + Two Cycles of Chemotherapy vs. Pembrolizumab + Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer.
Panpan Jiang, Ziyang Mao, +7 authors, Hui Guo.
Front Oncol, 2021 Oct 01; 11. PMID: 34589422    Free PMC article.
Systematic Review.
Impact of Anti-PD-1 and Anti-CTLA-4 on the Human Immunodeficiency Virus (HIV) Reservoir in People Living With HIV With Cancer on Antiretroviral Therapy: The AIDS Malignancy Consortium 095 Study.
Thomas A Rasmussen, Lakshmi Rajdev, +16 authors, Sharon R Lewin.
Clin Infect Dis, 2021 Mar 08; 73(7). PMID: 33677480    Free PMC article.
Emerging concepts in PD-1 checkpoint biology.
Kristen E Pauken, James A Torchia, +2 authors, Gordon J Freeman.
Semin Immunol, 2021 May 20; 52. PMID: 34006473    Free PMC article.
Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment.
Sumit K Subudhi, Bilal A Siddiqui, +10 authors, Padmanee Sharma.
J Immunother Cancer, 2021 Oct 20; 9(10). PMID: 34663638    Free PMC article.
Intratumoral DNA-based delivery of checkpoint-inhibiting antibodies and interleukin 12 triggers T cell infiltration and anti-tumor response.
Liesl Jacobs, Lidia Yshii, +4 authors, Paul Declerck.
Cancer Gene Ther, 2021 Nov 11;. PMID: 34754076
From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma.
Jonathan Anker, Justin Miller, +2 authors, Che-Kai Tsao.
Cells, 2021 Nov 28; 10(11). PMID: 34831452    Free PMC article.
Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response.
Anastasia Gangaev, Elisa A Rozeman, +11 authors, Pia Kvistborg.
Proc Natl Acad Sci U S A, 2021 Oct 22; 118(43). PMID: 34670835    Free PMC article.
T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy.
Elien De Bousser, Nico Callewaert, Nele Festjens.
Cancers (Basel), 2021 Dec 11; 13(23). PMID: 34885176    Free PMC article.
Reactive Oxygen Species: Do They Play a Role in Adaptive Immunity?
Esen Yonca Bassoy, Michael Walch, Denis Martinvalet.
Front Immunol, 2021 Dec 14; 12. PMID: 34899706    Free PMC article.
Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer.
Chang Gon Kim, Gamin Kim, +8 authors, Hye Ryun Kim.
J Immunother Cancer, 2021 Dec 16; 9(12). PMID: 34907028    Free PMC article.
Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy.
Myriam Ben Khelil, Yann Godet, +3 authors, Romain Loyon.
Cancers (Basel), 2022 Jan 12; 14(1). PMID: 35008422    Free PMC article.
Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression.
Shu-Chin Alicia Lai, Harika Gundlapalli, +3 authors, Alana L Welm.
Cancer Discov, 2021 Aug 01; 11(12). PMID: 34330779    Free PMC article.
Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject 'cold' tumors.
Monika Semmrich, Jean-Baptiste Marchand, +15 authors, Björn Frendéus.
J Immunother Cancer, 2022 Jan 22; 10(1). PMID: 35058324    Free PMC article.
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.
Tina Cascone, William N William, +50 authors, Boris Sepesi.
Nat Med, 2021 Feb 20; 27(3). PMID: 33603241    Free PMC article.
Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses.
Claire F Friedman, Christine Spencer, +17 authors, Jedd Wolchok.
J Immunother Cancer, 2022 Jan 26; 10(1). PMID: 35074903    Free PMC article.
Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy.
Lingyue Liu, Xing Huang, +5 authors, Xueli Bai.
J Exp Clin Cancer Res, 2022 Feb 11; 41(1). PMID: 35139879    Free PMC article.
Sweet Immune Checkpoint Targets to Enhance T Cell Therapy.
Nohelly Derosiers, William Aguilar, David A DeGaramo, Avery D Posey.
J Immunol, 2022 Jan 13; 208(2). PMID: 35017217    Free PMC article.
Monoclonal Antibodies to CTLA-4 with Focus on Ipilimumab.
Grazia Graziani, Lucia Lisi, Lucio Tentori, Pierluigi Navarra.
Exp Suppl, 2022 Feb 16; 113. PMID: 35165868
CytofIn enables integrated analysis of public mass cytometry datasets using generalized anchors.
Yu-Chen Lo, Timothy J Keyes, +10 authors, Kara L Davis.
Nat Commun, 2022 Feb 19; 13(1). PMID: 35177627    Free PMC article.
Independent Drug Action in Combination Therapy: Implications for Precision Oncology.
Deborah Plana, Adam C Palmer, Peter K Sorger.
Cancer Discov, 2022 Jan 06; 12(3). PMID: 34983746    Free PMC article.
[Dual Immunotherapy in Advanced Non-small Cell Lung Cancer: 
the Progress and Clinical Application].
Haiyi Deng, Liqiang Wang, +2 authors, Chengzhi Zhou.
Zhongguo Fei Ai Za Zhi, 2022 Mar 01; 25(2). PMID: 35224963    Free PMC article.
Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy.
Megan M Y Hong, Saman Maleki Vareki.
Cancers (Basel), 2022 Mar 26; 14(6). PMID: 35326731    Free PMC article.
Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response.
Tristan Rupp, Laurie Genest, +4 authors, Vincent Castagné.
Transl Oncol, 2022 Mar 28; 20. PMID: 35339889    Free PMC article.
[Advances in Immunotherapy for Malignant Pleural Mesothelioma].
Yujia Chi, Yiliang Liu, Jun Zhao.
Zhongguo Fei Ai Za Zhi, 2022 Apr 29; 25(4). PMID: 35477190    Free PMC article.
Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities.
Tae Kon Kim, Esten N Vandsemb, Roy S Herbst, Lieping Chen.
Nat Rev Drug Discov, 2022 Jun 15;. PMID: 35701637
Immuno-reactive cancer organoid model to assess effects of the microbiome on cancer immunotherapy.
Ethan Shelkey, David Oommen, +5 authors, Shay Soker.
Sci Rep, 2022 Jun 16; 12(1). PMID: 35705580