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Prophylaxis with abemaciclib delays tumorigenesis in dMMR mice by altering immune responses and reducing

Annabell Wolff¹, Paula Krone¹, Johanna Maennicke¹

¹Department of Medicine, Clinic III -Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.

Translational Oncology

|July 10, 2024

Abstract

Background:

The CDK4/6 inhibitor abemaciclib is an FDA-approved agent and induces T-cell-mediated immunity. Previously, we confirmed the therapeutic potential of abemaciclib on mismatch repair-deficient (dMMR) tumors in mice. Here, we applied a prophylactic administration/dosage setting using two preclinical mouse models of dMMR-driven cancer.

Methods:

Mlh1^-/- and Msh2^loxP/loxP mice received repeated prophylactic applications of abemaciclib mesylate (75 mg/kg bw, per oral) as monotherapy or were left untreated. Blood phenotyping and multiplex cytokine measurements were performed regularly. The tumor microenvironment was evaluated by immunofluorescence and Nanostring-based gene expression profiling. Numbers, size and immune composition and activity of extracellular vesicles (EVs) were studied at the endpoint.

Findings:

Prophylactic abemaciclib-administration delayed tumor development and significantly prolonged overall survival in both mouse strains (Mlh1^-/-: 50.0 wks vs. control: 33.9 wks; Msh2^{loxP/loxP;TgTg(Vil1-cre}: 58.4 wks vs. control 44.4 wks). In Mlh1^-/- mice, pro-inflammatory cytokines (IL-2, IL-6) significantly increased, whereas IL-10 and IL-17A decreased. Circulating and splenic exhausted and regulatory T cell numbers were significantly lower in the abemaciclib groups. Deeper analysis of late-onset tumors revealed activation of the Hedgehog and Notch signaling in Mlh1^-/- mice, and activation of the MAPK pathway in Msh2^{loxP/loxP;TgTg(Vil1-cre} mice. Still, arising tumors had fewer infiltrating myeloid-derived suppressor cells (vs. control). Notably, prophylactic abemaciclib-administration prevented secretion of procoagulant EVs but triggered release of immunomodulatory EVs in Mlh1^-/- mice.

Interpretation:

Prophylactic abemaciclib prolongs survival via global immunomodulation. Prophylactic use of abemaciclib should be considered further for individuals with inherited dMMR.

Funding:

This work was supported by grants from the German research foundation [DFG grant number: MA5799/2-2] and the Brigitte und Dr. Konstanze Wegener-Stiftung to CM.

Insights

Prophylactic abemaciclib administration significantly prolonged survival in preclinical models of mismatch repair-deficient (dMMR) cancers by modulating the immune system. This suggests potential for inherited dMMR cancer prevention.

Area of Science:

Oncology
Immunology
Cancer Biology

Background:

Abemaciclib, a CDK4/6 inhibitor, enhances T-cell immunity and shows therapeutic potential in mismatch repair-deficient (dMMR) tumors.
Preclinical mouse models of dMMR-driven cancer were utilized to investigate prophylactic abemaciclib administration.

Purpose of the Study:

To evaluate the efficacy of prophylactic abemaciclib administration in delaying tumor development and prolonging survival in dMMR cancer models.
To investigate the immunomodulatory effects of prophylactic abemaciclib on the tumor microenvironment and systemic immunity.

Main Methods:

Mice with dMMR (Mlh1-/- and Msh2loxP/loxP) received prophylactic abemaciclib or were untreated.
Blood phenotyping, cytokine analysis, immunofluorescence, Nanostring gene expression, and extracellular vesicle (EV) profiling were performed.

Main Results:

Prophylactic abemaciclib significantly delayed tumor onset and prolonged overall survival in both dMMR mouse models.
Abemaciclib modulated cytokine profiles, reduced exhausted/regulatory T cells, and decreased myeloid-derived suppressor cells in tumors.
Prophylactic abemaciclib altered EV profiles, preventing procoagulant EVs and promoting immunomodulatory EVs.

Conclusions:

Prophylactic abemaciclib demonstrates significant survival benefits in dMMR cancer models through broad immunomodulation.
These findings support further investigation of prophylactic abemaciclib for individuals with inherited dMMR predispositions.

Read full analysis

Keywords:

Cell cycle regulation Clotting Hereditary cancer prevention Immune modulation

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