Mechanism-and immune landscape-based ranking of therapeutic responsiveness of 22 major human cancers to next generation anti-CTLA-4 antibodies
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AbstractBackground: 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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
SponsorsThis work is supported by NIH grant AI64350 (to Y.L. and P.Z.) and CA227671 (to P.Z.), Melanoma Research Alliances (MRATSA 559400, to P.Z.), a grant from OncoImmune, Inc (to Y.L.). The study involving human lung cancer tissues was supported by grants (to P.Z.) from the National Key Research and Development Program of China (No. 2016YFA0500304), the Sci-Tech Project Foundation of Guangzhou City (201607020038), the National Nature Science Foundation in China (NSFC) (81572806, 81773052), the Science and technology projects of Guangdong. Province (2016A020215086), the Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638), and the leading talents of Guangdong province program.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85078764093&doi=10.3390%2fcancers12020284&partnerID=40&md5=1d9e3d3447474fcfce47a1fc1fd4bea3; http://hdl.handle.net/10713/11988