Spatial heterogeneity of immune regulators drives dynamic changes of local immune responses, affecting disease outcomes in pancreatic cancer.

Karamitopoulou, Eva; Wenning, Anna Silvia; Acharjee, Animesh; Aeschbacher, Pauline; Marinoni, Ilaria; Zlobec, Inti; Gloor, Beat; Perren, Aurel (2024). Spatial heterogeneity of immune regulators drives dynamic changes of local immune responses, affecting disease outcomes in pancreatic cancer. Clinical cancer research, 30(18), pp. 4215-4226. American Association for Cancer Research 10.1158/1078-0432.CCR-24-0368

[img] Text
cjae032.pdf - Accepted Version
Restricted to registered users only until 15 July 2025.
Available under License Publisher holds Copyright.
Download (743kB)

PURPOSE

Pancreatic ductal adenocarcinoma (PDAC) is considered a low immunogenic tumor with "cold" tumor microenvironment (TME) and is mostly unresponsive to immune checkpoint blockade therapies. Here we decipher the impact of intratumoral heterogeneity of immune determinants on antitumor response.

EXPERIMENTAL DESIGN

We performed spatial proteomic and transcriptomic analyses and multiplexed immunofluorescence on multiple tumor regions, including tumor center (TC) and invasive front (IF), from 220 PDAC-patients, classified according to their transcriptomic immune signaling into high-immunogenic (HI-PDACs, n=54) and low-immunogenic tumors (LI-PDACs, n=166). Spatial compartments (tumor: Pancytokeratin+/CD45- and leukocytes: Pancytokeratin-/CD45+) were defined by fluorescent imaging.

RESULTS

HI-PDACs exhibited higher densities of cytotoxic T lymphocytes with upregulation of T-cell priming-associated immune determinants, including CD40, ITGAM, GITR, CXCL10, GZMB, IFNG and HLA-DR, which was significantly more prominent at the IF than the TC. In contrast, LI-PDACs exhibited immune evasive TMEs with downregulation of immune determinants and a negative gradient from TC to IF. Patients with HI-PDACs had significantly better outcomes; however, they showed more frequently exhausted immune phenotypes.

CONCLUSIONS

Our results indicate strategic differences in the regulation of immune determinants, which lead to different levels of effectiveness of antitumor responses between high- and low-immunogenic tumors and dynamic spatial changes, which affect the evolution of immune evasion and patient outcomes. This supports coevolution of tumor and immune cells and may help define therapeutic vulnerabilities to improve antitumor immunity and harness the responsiveness to immune checkpoint inhibitors in PDAC patients.

Item Type:

 Journal Article (Original Article)

Division/Institute:

 ?? 466EAF1B54364F4FADA2E68A076E7AAD ??
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine

UniBE Contributor:

 Karamitopoulou Diamantis, Evanthia, Wenning, Anna Silvia, Aeschbacher, Pauline, Marinoni, Ilaria, Zlobec, Inti, Gloor, Beat, Perren, Aurel

Subjects:

 500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

 1078-0432

Publisher:

 American Association for Cancer Research

Language:

 English

Submitter:

 Pubmed Import

Date Deposited:

 16 Jul 2024 13:32

Last Modified:

 14 Sep 2024 00:14

Publisher DOI:

 10.1158/1078-0432.CCR-24-0368

PubMed ID:

 39007872

BORIS DOI:

 10.48350/199026

URI:

 https://boris.unibe.ch/id/eprint/199026

Actions (login required)

Edit item Edit item
Provide Feedback