Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab
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Ilyas Sahin1,2,3,4,9,*, Andrew George1,*, Shengliang Zhang1,2,4,5,*, Kelsey E. Huntington1,6, Zehra Ordulu7,9, Lanlan Zhou1,2,4,5 and Wafik S. El-Deiry1,2,3,4,5,6,8
1 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School of Brown University, Providence, RI, USA
2 Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA
3 Division of Hematology/Oncology, The Warren Alpert Medical School of Brown University, Providence, RI, USA
4 Cancer Center at Brown University, The Warren Alpert Medical School of Brown University, Providence, RI, USA
5 Department of Pathology & Laboratory Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA
6 Pathobiology Graduate Program, Warren Alpert Medical School of Brown University, Providence, RI, USA
7 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
8 Molecular and Cellular Biology Graduate Program, The Warren Alpert Medical School of Brown University, Providence, RI, USA
9 Present Address: University of Florida Health Cancer Center, Gainesville, FL, USA
* These authors contributed equally to this work
|Wafik S. El-Deiry,||email:||firstname.lastname@example.org|
Keywords: cancer immunotherapy; immune checkpoint inhibitors; hyperprogressive disease (HPD); hyperprogression (HP); humanized mouse
Received: September 07, 2021 Accepted: September 18, 2021 Published: October 12, 2021
Immunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient (MMR-d) human colon carcinoma HCT116 p53-null (but not wild-type p53) tumor xenograft, we observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration. There was increased colon tumor cell proliferation as determined by immunohistochemical Ki67 staining of tumor sections. There was no increase in MDM2 or MDM4/MDMX in the p53-null HCT116 cells versus the wild-type p53-expressing isogenic tumor cells, suggesting the effects in this model may be MDM2 or MDM4/MDMX-independent. Human cytokine profiling revealed changes in IFN-γ, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-α. This represents a novel humanized HPD mouse model with a link to deficiency of the p53 pathway of tumor suppression in the setting of MMR-d. Our novel humanized preclinical TALL-104/p53-null HCT116 mouse model implicates p53-deficiency in an MMR-d tumor as a possible contributor to HPD/HP and may help with evaluating therapeutic strategies in cancer immunotherapy to extend clinical benefits of ICB’s in a broader patient population.
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