Different syngeneic tumors show distinctive intrinsic tumor-immunity and mechanisms of actions (MOA) of anti-PD-1 treatment
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Cancers are immunologically heterogeneous. A range of immunotherapies target abnormal tumor immunity via different mechanisms of actions (MOAs), particularly various tumor-infiltrate leukocytes (TILs). We modeled loss of function (LOF) in four common anti-PD-1 antibody-responsive syngeneic tumors, MC38, Hepa1-6, CT-26 and EMT-6, by systematical depleting a series of TIL lineages to explore the mechanisms of tumor immunity and treatment. CD8 + -T-cells, CD4 + -T-cells, T reg , NK cells and macrophages were individually depleted through either direct administration of anti-marker antibodies/reagents or using DTR (diphtheria toxin receptor) knock-in mice, for some syngeneic tumors, where specific subsets were depleted following diphtheria toxin (DT) administration. These LOF experiments revealed distinctive intrinsic tumor immunity and thus different MOAs in their responses to anti-PD-1 antibody among different syngeneic tumors. Specifically, the intrinsic tumor immunity and the associated anti-PD-1 MOA were predominately driven by CD8 + cytotoxic TILs (CTL) in all syngeneic tumors, excluding Hepa1-6 where CD4 + T eff TILs played a key role. TIL-T reg also played a critical role in supporting tumor growth in all four syngeneic models as well as M 2 -macrophages. Pathway analysis using pharmacodynamic readouts of immuno-genomics and proteomics on MC38 and Hepa1-6 also revealed defined, but distinctive, immune pathways of activation and suppression between the two, closely associated with the efficacy and consistent with TIL-pharmacodynamic readouts. Understanding tumor immune-pathogenesis and treatment MOAs in the different syngeneic animal models, not only assists the selection of the right model for evaluating new immunotherapy of a given MOA, but also can potentially help to understand the potential disease mechanisms and strategize optimal immune-therapies in patients.
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The authors previously performed in vivo combination studies using anti-PD-1 antibody and five depleting agents in four syngeneic models, showing different mechanisms of action under anti-PD-1 treatment.
“We previously performed a series of in vivo combination studies using an anti-mouse PD-1 antibody and one of five other antibodies/agents that deplete CD8+ T cells, CD4+ T cells, regulatory T (Treg) cells, natural killer (NK) cells, and tumor-associated macrophages (TAM), respectively, in four anti-PD-1 antibody-responsive syngeneic models to show that they have different mechanisms of actions”
From Statistical Assessment of Drug Synergy from <i>In Vivo</i> Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [35]
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- Authors
- Jin, Y., An, X., Mao, B., Sun, R., Kumari, R., Chen, X., Shan, Y., Zang, M., Xu, L., Muntel, J., Beeler, K., Bruderer, R., Reiter, L., Guo, S., Zhou, D., Li, Q.-X., & Ouyang, X.
- Affiliations
- Peking University (CN)
- Shanghai Model Organisms (China) (CN)
- Biognosys (Switzerland) (CH)
- Corresponding author
- Li, Qi-Xiang
- Ouyang, Xuesong
- ORCID
- Venue
- Scientific Reports
- Published
- 2022-02-28
- Volume
- 12
- Issue
- 1
- Pages
- 3278-3278
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8885837
- OpenAlex
- W4214541685
- Cited by
- 73
- References
- 45
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 21 · 2023: 19 · 2022: 2
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Greater South Information System
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- anti-PD-1 therapy, mechanism of action, tumor-infiltrating lymphocytes, syngeneic mouse model, CD8+ cytotoxic T lymphocytes, CD4+ T cells, regulatory T cells, natural killer cells, tumor-associated macrophages, M2 macrophages, T cell depletion, MC38 colon carcinoma, CT26 cells, tumor immune microenvironment
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Cell Line, Tumor, T-Lymphocytes, Regulatory, Mice, Tumor Microenvironment
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