Regulation of pancreatic cancer therapy resistance by chemokines

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by high resistance and poor response to chemotherapy. In addition, the poorly immunogenic pancreatic tumors constitute an immunosuppressive tumor microenvironment (TME) that render immunotherapy-based approaches ineffective. Understanding the mechanisms of therapy resistance, identifying new targets, and developing effective strategies to overcome resistance can significantly impact the management of PDAC patients. Chemokines are small soluble factors that are significantly deregulated during PDAC pathogenesis, contributing to tumor growth, metastasis, immune cell trafficking, and therapy resistance. Thus far, different chemokine pathways have been explored as therapeutic targets in PDAC, with some promising results in recent clinical trials. Particularly, immunotherapies such as immune check point blockade therapies and CAR-T cell therapies have shown promising results when combined with chemokine targeted therapies. Considering the emerging pathological and clinical significance of chemokines in PDAC, we reviewed major chemokine-regulated pathways leading to therapy resistance and the ongoing endeavors to target chemokine signaling in PDAC. This review discusses the role of chemokines in regulating therapy resistance in PDAC and highlights the continuing efforts to target chemokine-regulated pathways to improve the efficacy of various treatment modalities.

Keywords: Chemokine-signaling; Immunosuppression; Pancreatic ductal adenocarcinoma; Therapy resistance; Tumor microenvironment.

Figure 1:. Role of chemokines in pancreatic cancer therapy resistance.

(A) The crosstalk between cancer and stromal cells occurs through chemokines (colored dots) leading to the evolution of therapy resistant pancreatic TME. Chemokine gradient in the pancreatic TME facilitates chemotaxis and immune cell infiltration. The infiltrating immune cells together with stromal cells (CAFs) and cancer cells contribute to the chemokine pool that further exacerbate therapy resistance. (B) Both autocrine and paracrine chemokine signaling occurs in pancreatic TME to induce chemotherapy resistance in PC cells. The highly abundant CAFs and TAMs are shown as representative stromal cell populations that secrete chemokines and regulate different pathways (arrows) promoting chemotherapy resistance. (C) Radiation-induced DNA damage and deregulated repair mechanism cause radiotherapy resistance. The reactive oxygen species (ROS) induce upregulation of chemokines and radioresistance. Representative chemokines are shown in the figure (red) (D) Immune cell specific chemokine axes involving various regulatory immune cells are shown in the box. The stromal chemokine pool induces MHC downregulation and upregulation of immune checkpoints such as PD-L1, resulting in poor antigen presentation and immunosuppression. Chemokines influencing the infiltrating T cells and high expression on immune checkpoints on regulatory T cell are shown on right side. Abbreviations: TME: Tumor microenvironment; C-C: Chemokine; TAM: tumor associated macrophage; CAF: Cancer associated fibroblast; MDSCs: Myeloid derived suppressor cells; PD-1: Programmed death receptor-1; PD-L1: Programmed death receptor ligand-1; LAG-3: Lymphocyte activation gene-3; TIM3: T-cell Immunoglobulin domain and Mucin domain 3; VISTA: V-domain Ig suppressor of T cell activation; TIGIT: T cell immunoreceptor with Ig and ITIM domains.

Figure 2:. Upregulated chemokine targets contributing to therapy resistance in PDAC.

Upregulated chemokines and receptors play a pivotal role in therapy resistance, including chemotherapy, radiotherapy, and immunotherapy. The CXCR4-CXCL12 chemokine axis is highlighted in red to show its upregulation in all the treatment modalities, suggesting its universal role in therapy resistance in PDAC. Dots denote the upregulated chemokines post-therapy (image was created on Biorender).

Figure 3:. Therapeutic approaches targeting chemokine axis in PDAC.

Analysis of chemokine levels following first-line therapies in resectable/borderline resectable (A) and in non-resectable (B) PDAC patients. Proposed chemokine profiling in patients is included after R1-R2 evaluation to rationalize chemokine therapies in selective PDAC patients. R1-R2 evaluation represents response and recurrence after the therapy. *Known chemokine pathways that have been evaluated in clinical trials involving PDAC patients. ** Alternative chemotherapy includes: FOLFIRINOX/mFOLFIRINOX or Gem + nab-paclitaxel. Chemo- Chemotherapy; CRT- radiotherapy; ICB- immune checkpoint blockade therapy.