Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies
Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immu...
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| Format: | Article |
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MDPI AG
2020-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/2/284 |
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| author | Peng Zhang Xinxin Xiong Christian Rolfo Xuexiang Du Yan Zhang Han Yang Alessandro Russo Martin Devenport Penghui Zhou Yang Liu Pan Zheng |
| author_facet | Peng Zhang Xinxin Xiong Christian Rolfo Xuexiang Du Yan Zhang Han Yang Alessandro Russo Martin Devenport Penghui Zhou Yang Liu Pan Zheng |
| author_sort | Peng Zhang |
| collection | DOAJ |
| description | Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated. To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment. Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP). A major unresolved issue is how to select appropriate cancer types for future clinical development. Methods: We generated a landscape of the immune tumor microenvironment from RNAseq and genomic data of 7279 independent cancer samples belonging to 22 cancer types from The Cancer Genomics Atlas (TCGA) database. Based primarily on genomic and RNAseq data from pre-treatment clinical samples of melanoma patients who were later identified as responders and nonresponders to the anti-CTLA-4 antibody Ipilimumab, we identified 5 ranking components of responsiveness to anti-CTLA-4, including CTLA-4 gene expression, ADCC potential, mutation burden, as well as gene enrichment and cellular composition that favor CTLA-4 responsiveness. The total ranking number was calculated by the sum of 5 independent partitioning values, each comprised of 1−3 components. Results: Our analyses predict metastatic melanoma as the most responsive cancer, as expected. Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies. Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg. Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies. Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies. The comprehensive ranking of major cancer types provides a roadmap for clinical development of the next generation of anti-CTLA-4 antibodies. |
| first_indexed | 2024-03-12T06:33:05Z |
| format | Article |
| id | doaj.art-8760cd6cac934fff99e9663048a98f39 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:33:05Z |
| publishDate | 2020-01-01 |
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| series | Cancers |
| spelling | doaj.art-8760cd6cac934fff99e9663048a98f392023-09-03T01:29:58ZengMDPI AGCancers2072-66942020-01-0112228410.3390/cancers12020284cancers12020284Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 AntibodiesPeng Zhang0Xinxin Xiong1Christian Rolfo2Xuexiang Du3Yan Zhang4Han Yang5Alessandro Russo6Martin Devenport7Penghui Zhou8Yang Liu9Pan Zheng10Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USAKey Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, ChinaGreenebaum Comprehensive Cancer Center, Experimental Therapeutics Program, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USADivision of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USADivision of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USAKey Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, ChinaGreenebaum Comprehensive Cancer Center, Experimental Therapeutics Program, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USAOncoImmune, Inc.Rockville, MD 20850, USAKey Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, ChinaDivision of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USADivision of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USABackground: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated. To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment. Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP). A major unresolved issue is how to select appropriate cancer types for future clinical development. Methods: We generated a landscape of the immune tumor microenvironment from RNAseq and genomic data of 7279 independent cancer samples belonging to 22 cancer types from The Cancer Genomics Atlas (TCGA) database. Based primarily on genomic and RNAseq data from pre-treatment clinical samples of melanoma patients who were later identified as responders and nonresponders to the anti-CTLA-4 antibody Ipilimumab, we identified 5 ranking components of responsiveness to anti-CTLA-4, including CTLA-4 gene expression, ADCC potential, mutation burden, as well as gene enrichment and cellular composition that favor CTLA-4 responsiveness. The total ranking number was calculated by the sum of 5 independent partitioning values, each comprised of 1−3 components. Results: Our analyses predict metastatic melanoma as the most responsive cancer, as expected. Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies. Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg. Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies. Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies. The comprehensive ranking of major cancer types provides a roadmap for clinical development of the next generation of anti-CTLA-4 antibodies.https://www.mdpi.com/2072-6694/12/2/284anti-ctla-4 antibodylung cancerimmunotherapy responsivenesstcgatregadcc/adcpirae |
| spellingShingle | Peng Zhang Xinxin Xiong Christian Rolfo Xuexiang Du Yan Zhang Han Yang Alessandro Russo Martin Devenport Penghui Zhou Yang Liu Pan Zheng Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies Cancers anti-ctla-4 antibody lung cancer immunotherapy responsiveness tcga treg adcc/adcp irae |
| title | Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies |
| title_full | Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies |
| title_fullStr | Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies |
| title_full_unstemmed | Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies |
| title_short | Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies |
| title_sort | mechanism and immune landscape based ranking of therapeutic responsiveness of 22 major human cancers to next generation anti ctla 4 antibodies |
| topic | anti-ctla-4 antibody lung cancer immunotherapy responsiveness tcga treg adcc/adcp irae |
| url | https://www.mdpi.com/2072-6694/12/2/284 |
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