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Review
. 2024 May 16:15:1341079.
doi: 10.3389/fimmu.2024.1341079. eCollection 2024.

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

Chiara Musiu  1 , Francesca Lupo  2 , Antonio Agostini  3   4 , Gabriella Lionetto  5 , Michele Bevere  6 , Salvatore Paiella  5 , Carmine Carbone  4 , Vincenzo Corbo  2 , Stefano Ugel  1 , Francesco De Sanctis  1
Affiliations
Review

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

Chiara Musiu et al. Front Immunol. .

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.

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Conflict of interest statement

Paiella S. receives consultancy fees from AlphaTau. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
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
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.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was jointly supported by PRIN programs of the Italian Ministry of Education, University, and Research (MIUR, PI: De Sanctis F., CUP: B39J22001200001); AIRC (PI: Carbone C Grant No. 23681; PI: Corbo V. Grant No. 18178, PI: Ugel S. Grant No. 21509 and 28730); EU (MSCA project PRECODE, PI: Corbo V. Grant No 861196); PNRR programs of the Italian MUR (Project “National Center for Gene Therapy and Drugs based on RNA Technology”, application code CN00000041, Mission 4, Component 2 Investment 1.4, funded from the European Union - NextGenerationEU, MUR Directorial Decree No. 1035 of 17 June 2022, CUP B33C22000630001; PI: Ugel S). CM was supported by an AIRC fellowship for Italy (Call 2022), and was supported by Fondazione Umberto Veronesi (Call 2023). MB was supported by AIRC fellowships for Italy (28054; 29829).