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Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.

Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.

Authors :
Knudsen ES
Kumarasamy V
Chung S
Ruiz A
Vail P
Tzetzo S
Wu J
Nambiar R
Sivinski J
Chauhan SS
Seshadri M
Abrams SI
Wang J
Witkiewicz AK
Source :
Gut [Gut] 2021 Jan; Vol. 70 (1), pp. 127-138. Date of Electronic Publication: 2020 May 18.
Publication Year :
2021

Abstract

Objective: This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.<br />Design: Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment.<br />Results: We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors.<br />Conclusions: Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Details

Language :
English
ISSN :
1468-3288
Volume :
70
Issue :
1
Database :
MEDLINE
Journal :
Gut
Publication Type :
Academic Journal
Accession number :
32424005
Full Text :
https://doi.org/10.1136/gutjnl-2020-321000