The Chemokine CXCL14 as a Potential Immunotherapeutic Agent for Cancer Therapy

Abstract

There is great enthusiasm toward the development of novel immunotherapies for the treatment of cancer, and given their roles in immune system regulation, chemokines stand out as promising candidates for use in new cancer therapies. Many previous studies have shown how chemokine signaling pathways could be targeted to halt cancer progression. We and others have revealed that the chemokine CXCL14 promotes antitumor immune responses, suggesting that CXCL14 may be effective for cancer immunotherapy. However, it is still unknown what mechanism governs CXCL14-mediated antitumor activity, how to deliver CXCL14, what dose to apply, and what combinations with existing therapy may boost antitumor immune responses in cancer patients. Here, we provide updates on the role of CXCL14 in cancer progression and discuss the potential development and application of CXCL14 as an immunotherapeutic agent.

Keywords: CXCL14; chemokine; immunotherapy.

Figure 1

Classification of CXCL14 gene-to-functions. The functions and pathways associated with CXCL14 expression were analyzed using QIAGEN Ingenuity Pathway Analysis (IPA) (QIAGEN Inc. Redwood City, CA, USA, https://digitalinsights.qiagen.com/IPA (accessed on 21 May 2023)) and plotted in a colored circle. Blue and red segments correspond to increased and decreased functions and pathways relative to increased CXCL14 expression, respectively. The articles were collected from IPA analysis and then categorized into four broad groups (center pie chart) [34,36,46,52,53,55,56,57,58,59,60,61,62,63,64].

Figure 2

In silico structural analysis of wildtype and mutant CXCL14 proteins. Predicted folding representation of wildtype CXCL14, CXCL14-RY43/44AA, and CXCL14-dEE proteins were generated in ColabFold (v. 1.5.2), based on AlphaFold2 [91,92]. Full protein structures are shown, along with detailed representations of mutated regions (red boxes) generated in SWISS-MODEL Workspace [93,94,95,96,97]. AlphaFold-predicted local distance difference test (pLDDT) represents a per-residue confidence score for each amino acid in the full peptide corresponding to the colored key.

Figure 3

Protein stability of wildtype and mutant CXCL14 proteins. (A) Western blots with whole cell lysate prepared from 293T cells transiently transfected with wild type CXCL14 (CXCL14-WT), CXCL14 with RY43/44AA substitution (CXCL14-RY43/44AA), or CXCL14 with the deletion of two glutamates at the C-terminus (CXCL14-dEE). After 24 h, cells were treated with MG-132 (10 µM) for 8 h and CHX (50 µg/mL) as previously described [99]. (B) Western blots with whole cell extract prepared from 293T cells transiently transfected with CXCL14-WT or CXCL14-RY43/44AA. After 24 h, cells were treated with MG-132, CHX, or Brefeldin A (5 µg/mL) as previously described [99]. Experimental diagrams created with BioRender.com.

Figure 4

Schematic strategy for activating antitumor CD8+ T-cell responses using CXCL14 combined with therapeutic HPV vaccines. (1) CXCL14 and T-cell epitope peptides are expressed in tumor cells. (2) The secretion of CXCL14 attracts T cells into the TME. (3) CXCL14 upregulates the presentation of the epitope peptides by MHC-I. (4) Increased CD8+ T-cell infiltration and MHC-I upregulation synergistically enhance tumor cell clearance by cytotoxic CD8+ T cells. Created with BioRender.com.