150P - Chemotherapy in combination with Toll-like receptor agonism promoted antitumor immune response in triple negative breast cancer

Background

Immunotherapy represents a promising research area for triple negative breast cancers (TNBCs), a breast cancer subtype defined by lack of estrogen and progesterone receptors, and HER2 overexpression. Current treatment is often limited to chemotherapy which is toxic and short lived with imminent metastatic recurrence. TNBCs are more immunogenic, often characterized by high number of tumors infiltrating lymphocytes, a feature which can be harnessed to increase responsiveness to immunotherapy. Immune cells are known to express pathogen recognition receptors such as toll-like receptors (TLRs) and their engagement activates downstream pathways to elicit specific T cell antitumor immunity.

Methods

To utilize immune modulation strategy for TNBC treatment, the study evaluated the combined efficacy of Paclitaxel with intratumoral administration of TLR7/8 (Resiquimod) or TLR9 (CPG-ODN-2395) agonists in syngeneic TNBC mouse model. Tumor volume was measured, and percentages of tumor immune cell infiltrates were determined by flow cytometry at endpoint. Gene expression studies were also carried out on excised tumors using qPCR.

Results

Showed chemotherapy with Resiquimod or CPG-ODN 2395 promoted significant tumor regression compared to chemotherapy alone. Also, Paclitaxel/Resiquimod treatment significantly increased influx of B-cells, pDCs, helper and cytotoxic T-cells, and reduced regulatory T-cells tumor infiltrates compared to Paclitaxel/CPG-ODN 2395 and chemotherapy alone. Furthermore, Paclitaxel/Resiquimod treatment significantly upregulated gene expression of chemokines attracting cytotoxic T lymphocytes, type-1 helper, and NK cells as well as increased gene expression of IFN-γ, perforin, and granzyme B. Vimentin and Claudin 5, genes associated with epithelial mesenchymal transition and metastasis respectively were downregulated following Paclitaxel/Resiquimod treatment.

Conclusions

Overall, findings suggest that combination therapy of TLR7/8 agonist (Resiquimod) with Paclitaxel, promotes antitumor immunity and may represent a more effective treatment approach for TNBC.

Legal entity responsible for the study

The authors.

Funding

Croucher innovative award.

Disclosure

All authors have declared no conflicts of interest.