Background: Pancreatic cancer (PC) is characterised by late diagnosis, tumour heterogeneity, and a peculiar immunosuppressive microenvironment, leading to poor clinical outcomes. Local ablative techniques have been proposed to treat unresectable PC patients, although their impact on activating the host immune system and overcoming resistance to immunotherapy remains elusive. Methods: We dissected the immune-modulatory abilities triggered by local ablation in mouse and human PC models and human specimens, integrating phenotypic and molecular technologies with functional assays. Results: Local ablation treatment performed in mice bearing orthotopic syngeneic PC tumours triggered tumour necrosis and a short-term inflammatory process characterised by the prompt increase of HMGB1 plasma levels, coupled with an enhanced amount of circulating and tumour infiltrating myeloid cells and increased MHCII expression in splenic myeloid antigen-presenting cells. Local ablation synergised with immunotherapy to restrict tumour progression and improved the survival of PC-bearing mice by evoking a T lymphocyte-dependent anti-tumour immune response. By integrating spatial transcriptomics with histological techniques, we pinpointed how combination therapy could reshape TME towards an anti-tumour milieu characterised by the preferential entrance and colocalization of activated T lymphocytes and myeloid cells endowed with antigen presentation features instead of T regulatory lymphocytes and CD206-expressing tumour-associated macrophages. In addition, treatment-dependent TME repolarisation extended to neoplastic cells, promoting a shift from squamous to a more differentiated classical phenotype. Finally, we validated the immune regulatory properties induced by local ablation in PC patients and identified an association of the short-term treatment-dependent increase of neutrophils, NLR and HMGB1 with a longer time to progression. Conclusion: Therefore, local ablation might overcome the current limitations of immunotherapy in PC.
Local ablation disrupts immune evasion in pancreatic cancer
Musiu, Chiara;Adamo, Annalisa;Caligola, Simone;Frusteri, Cristina;Lupo, Francesca;Boschi, Federico;Busato, Alice;Poffe, Ornella;Anselmi, Cristina;Vella, Antonio;Wang, Tian;Dusi, Silvia;Piro, Geny;Carbone, Carmine;Tortora, Giampaolo;Marzola, Pasquina;D'Onofrio, Mirko;Crinò, Stefano Francesco;Corbo, Vincenzo;Scarpa, Aldo;Salvia, Roberto;Malleo, Giuseppe;Lionetto, Gabriella;Sartoris, Silvia;Ugel, Stefano
;Bassi, Claudio;Bronte, Vincenzo;Paiella, Salvatore;De Sanctis, Francesco
2025-01-01
Abstract
Background: Pancreatic cancer (PC) is characterised by late diagnosis, tumour heterogeneity, and a peculiar immunosuppressive microenvironment, leading to poor clinical outcomes. Local ablative techniques have been proposed to treat unresectable PC patients, although their impact on activating the host immune system and overcoming resistance to immunotherapy remains elusive. Methods: We dissected the immune-modulatory abilities triggered by local ablation in mouse and human PC models and human specimens, integrating phenotypic and molecular technologies with functional assays. Results: Local ablation treatment performed in mice bearing orthotopic syngeneic PC tumours triggered tumour necrosis and a short-term inflammatory process characterised by the prompt increase of HMGB1 plasma levels, coupled with an enhanced amount of circulating and tumour infiltrating myeloid cells and increased MHCII expression in splenic myeloid antigen-presenting cells. Local ablation synergised with immunotherapy to restrict tumour progression and improved the survival of PC-bearing mice by evoking a T lymphocyte-dependent anti-tumour immune response. By integrating spatial transcriptomics with histological techniques, we pinpointed how combination therapy could reshape TME towards an anti-tumour milieu characterised by the preferential entrance and colocalization of activated T lymphocytes and myeloid cells endowed with antigen presentation features instead of T regulatory lymphocytes and CD206-expressing tumour-associated macrophages. In addition, treatment-dependent TME repolarisation extended to neoplastic cells, promoting a shift from squamous to a more differentiated classical phenotype. Finally, we validated the immune regulatory properties induced by local ablation in PC patients and identified an association of the short-term treatment-dependent increase of neutrophils, NLR and HMGB1 with a longer time to progression. Conclusion: Therefore, local ablation might overcome the current limitations of immunotherapy in PC.
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