Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC

Abstract

Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients.

Keywords: MDSC (myeloid-derived suppressor cells); PDAC - pancreatic ductal adenocarcinoma; TILs (tumor infiltrating lymphocytes); TME (tumor microenvironment); cancer associated fibroblast (CAF); immunosuppression; immunotherapy.

Figure 1

PDAC TME heterogeneity and organization. PDAC can be divided into different subtypes according to TME composition: tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) characterize the myeloid-enriched subtype; several cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) components determine the desmoplastic stroma typical of hypoinflammed subtype; infiltration of T cells is associated with the lymphoid-enriched subtype. The lymphoid enriched subtype holds a significant survival advantage compared to the myeloid-enriched and hypoinflamed subtype.

Figure 2

Therapy-induced reprogramming of PDAC TME. The combination of different therapeutic strategies can revert the hostile microenvironment towards an anti-tumor one. Four major therapeutic interventions are emerging to improve PDAC treatment: neoplastic cells, immune cells, stromal compartments and soluble mediators. Several approaches are focused on neoplastic cells and their genetic alterations (A). Moreover, the microenvironment that surrounds PDAC cells holds key insight into novel treatment options. The reprogramming of myeloid cells can relieve immune suppression (B) and coupled with increased antigen presentation allow the recruitment and priming of T cells. Another strategy is represented by the modulation of the desmoplastic stroma, such as cancer-associated fibroblasts (CAFs) (C). Given the double role of CAFs in the TME, reverting the tumor-promoting into quiescent cells represent the best strategy. Indeed, multiple cell types co-exist within the TME, and their communication occurs through soluble mediators (metabolites, cytokines, chemokines) (D). Targeting soluble mediators can hamper immune cells recruitment and pro-tumor differentiation, as well as deposition of extracellular matrix, thus limiting tumor progression.