The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity
| Autor: | Paul Kirschmeier, Jeffrey Liu, Andrew H. Beck, Catherine Ferrante, Sangeetha Palakurthi, Christopher Moy, Elena Ivanova, Mark A. Bittinger, Martha R. Gowaski, Abha Dhaneshwar, Dennis M. Bonal, Mari Kuraguchi, Matthew V. Lorenzi, Kwok-Kin Wong, Kristin Depeaux, Samuel N. Regan, Jessie M. English, Catherine Sanders, Raluca I. Verona, Julie A. Rytlewski, Pasi A. Jänne, Kathryn Packman, Dyane Bailey, Enrique Zudaire, Wei Huang, Sima Zacharek, Sylvie Laquerre, Aditya Khosla |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment FGFR Inhibition Programmed Cell Death 1 Receptor Immunology Receptors Antigen T-Cell Mice Transgenic Biology Immunophenotyping Targeted therapy Mice 03 medical and health sciences Antineoplastic Agents Immunological Lymphocytes Tumor-Infiltrating 0302 clinical medicine Immune system Downregulation and upregulation Erdafitinib T-Lymphocyte Subsets Cell Line Tumor Neoplasms Quinoxalines Tumor Microenvironment medicine Animals Humans Tumor microenvironment T-cell receptor Immunity Drug Synergism Prognosis Receptors Fibroblast Growth Factor Disease Models Animal Treatment Outcome 030104 developmental biology 030220 oncology & carcinogenesis Mutation Cancer research Pyrazoles Biomarkers Signal Transduction |
| Zdroj: | Cancer Immunology Research. 7:1457-1471 |
| ISSN: | 2326-6074 2326-6066 |
| Popis: | The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2K660N/p53mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti–PD-1 alone was ineffective, the erdafitinib and anti–PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRASG12C-mutant genetically engineered mouse model, which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumor-associated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased T-cell receptor (TCR) clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti–PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti–PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival. |
| Databáze: | OpenAIRE |
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