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Updated: Oct 2, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
TUSC2 immunogene enhances efficacy of chemo-immuno combination on KRAS/LKB1 mutant NSCLC in humanized mouse model
Ismail M Meraz1, Mourad Majidi2, RuPing Shao2
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. imeraz@mdanderson.org.
Abstract:
KRAS/LKB1 (STK11) NSCLC metastatic tumors are intrinsically resistant to anti-PD-1 or PD-L1 immunotherapy. In this study, we use a humanized mouse model to show that while carboplatin plus pembrolizumab reduce tumor growth moderately and transiently, the addition of the tumor suppressor gene TUSC2, delivered systemically in nanovesicles, to this combination, eradicates tumors in the majority of animals. Immunoprofiling of the tumor microenvironment shows the addition of TUSC2 mediates: (a) significant infiltration of reconstituted human functional cytotoxic T cells, natural killer cells, and dendritic cells; (b) induction of antigen-specific T cell responses; (c) enrichment of functional central and memory effector T cells; and (d) decreased levels of PD-1+ T cells, myeloid-derived suppressor cells, Tregs, and M2 tumor associated macrophages. Depletion studies show the presence of functional central and memory effector T cells are required for the efficacy. TUSC2 sensitizes KRAS/LKB1 tumors to carboplatin plus pembrolizumab through modulation of the immune contexture towards a pro-immune tumor microenvironment.
Insights
Adding TUSC2 gene therapy to carboplatin and pembrolizumab immunotherapy eradicates KRAS/LKB1-mutant NSCLC tumors. TUSC2 enhances anti-tumor immune responses, overcoming intrinsic resistance to immunotherapy.
Area of Science:
- Oncology
- Immunotherapy
- Gene Therapy
Background:
- KRAS/LKB1 (STK11) mutations confer intrinsic resistance to anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer (NSCLC).
- Effective therapeutic strategies are needed to overcome this resistance.
Purpose of the Study:
- To evaluate the efficacy of TUSC2 gene therapy combined with carboplatin and pembrolizumab in a humanized mouse model of KRAS/LKB1-mutant NSCLC.
- To investigate the immunomodulatory effects of TUSC2 in the tumor microenvironment.
Main Methods:
- Utilized a humanized mouse model with KRAS/LKB1-mutant NSCLC.
- Administered carboplatin plus pembrolizumab, with and without systemic TUSC2 delivered via nanovesicles.
- Conducted comprehensive immunoprofiling of the tumor microenvironment.
- Performed immune cell depletion studies.
Main Results:
- The combination of carboplatin, pembrolizumab, and TUSC2 eradicated tumors in the majority of animals, unlike carboplatin plus pembrolizumab alone.
- TUSC2 treatment significantly increased infiltration of cytotoxic T cells, NK cells, and dendritic cells.
- TUSC2 induced antigen-specific T cell responses and enriched functional effector T cells, while decreasing suppressive immune cells.
- Efficacy was dependent on the presence of functional effector T cells.
Conclusions:
- Systemic TUSC2 gene therapy sensitizes KRAS/LKB1-mutant NSCLC to carboplatin and pembrolizumab.
- TUSC2 reshapes the tumor immune microenvironment towards a pro-immune state, overcoming immunotherapy resistance.
- This combination strategy holds promise for treating refractory NSCLC.
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