Modulation of the tumor microenvironment in Head and Neck Squamous Cell Carcinoma (HNSCC)

Introduction:

Presence of cytotoxic CD8+ T cells (CTLs) in tumor microenvironment (TME) is critical for the effectiveness of immune therapies and patients' outcome, while regulatory T® cells and myeloid derived suppressor cells (MDSC) promote cancer progression.

Methods:

A unique tissue explant culture method was used for solid tumors. With this ex vivo culture model, the whole TME can be stimulated. mRNA measurements were performed and culture supernatants were analyzed for chemokine concentrations. Alternatively, monocyte-derived macrophages or adult fibroblasts were used in analogous experiments. Chemotaxis assays were performed using pre-activated CD8+ T-cells (top chamber) and supernatants from cancer specimens. Western blot experiments were used to evaluate the impact of NFκB.

Results:

We show that two TLR3 ligands, both activate human TLR3 pathway, involving TRAF3 and IRF-3, and induce IFNα, ISG-60 and CXCL10, thus promoting CTLs chemotaxis to the ex vivo-treated tumors. However, in contrast to poly I:C, rintatolimod does not activate human MAVS/helicase pathway, thus avoiding the NFκB- and TNFα-dependent induction of COX-2, and induction of IDO, IL-10, CCL22 and CXCL12.

Conclusions:

With this work we have shown that a selective targeting of TLR3 and elimination of the NFkB-COX-2-TNFa pathway may allow for selective enhancement of type-1 immunity in human TME. The next steps will be to test other immunomodulating adjuvants as Checkpoint Inhibitors in HNSCC explant cultures and their effects on a) NFκB pathway, b) induction of a type-1 immunity with c) enhancement of the desired CTL attracting chemokines instead of Treg and MDSC attracting ones.

Publication History

Publication Date:
23 April 2019 (online)