TY - JOUR
T1 - p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
AU - Faget, Douglas V.
AU - Luo, Xianmin
AU - Inkman, Matthew J.
AU - Ren, Qihao
AU - Su, Xinming
AU - Ding, Kai
AU - Waters, Michael R.
AU - Raut, Ganesh Kumar
AU - Pandey, Gaurav
AU - Dodhiawala, Paarth B.
AU - Ramalho-Oliveira, Renata
AU - Ye, Jiayu
AU - Cole, Thomas
AU - Murali, Bhavna
AU - Zheleznyak, Alexander
AU - Shokeen, Monica
AU - Weiss, Kurt R.
AU - Monahan, Joseph B.
AU - Deselm, Carl J.
AU - Lee, Adrian V.
AU - Oesterreich, Steffi
AU - Weilbaecher, Katherine N.
AU - Zhang, Jin
AU - Denardo, David G.
AU - Stewart, Sheila A.
N1 - Funding Information:
This work was supported by NIH grants R01 AG059244, CA217208 (S.A. Stewart), and CA248493 (M. Shokeen), an American Cancer Society Research Scholar Award (S.A. Stewart), S10OD028483 (A.V. Lee), and a Komen Foundation Career Catalyst Award CCR18548418 (S. Oesterreich). This project used the Pitt Biospecimen Core/UPMC Hillman Cancer Center Tissue and Research Pathology Services supported in part by NIH grant award (grant number P30CA047904). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD, is the awarding and administrating acquisition office, and this was supported in part by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program, under award No. BC181712. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. This work was also supported by the Siteman Cancer Center Investment Program (NCI Cancer Center Support Grant P30CA091842, Fashion Footwear Association of New York, and the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund) to S.A. Stewart, and a Centene Corporation contract (P19-00559) for the Washington University-Centene ARCH Personalized Medicine Initiative (S.A. Stewart). P.B. Dodhiawala was supported by an NIH MSTP T32 GM008244 training grant under the Medical Scientist Training Program at the University of Minnesota Medical School, Minneapolis, MN. J. Ye was supported by NIH T32CA113275 and F31CA271721-01. We thank Roberta Faccio and Grant Challen for their valuable suggestions and Illaria Malanchi for the pRRL-sLPmCherry construct. We also thank Erica Lantelme and Dorjan Brinja in the Flow Cytometry and Fluorescence Activated Cell Sorting Pathology Core and Daniel Schweppe in the Siteman Flow Cytometry Core for help with sorting; Julie Prior and Katie Duncan in the Molecular Imaging Center for their help with bioluminescence imaging; and Graham Hogg from David DeNardo’s group for his help with antibody conjugation and cocktail preparation for mass cytometry. In addition, we thank the Genome Technology Access Center (GTAC) in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Centers are partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant #UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. Image acquisition for IHC analyses was performed in part through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770 and 4642). We also thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO, for the use of the Immunomonitoring Laboratory, which provided support for data acquisition from the CyTOF2/Helios mass cytometer and access to BD LSRFortessa X20 flow cytometer. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA091842.
Funding Information:
D.V. Faget reports a patent for 63/479,890 pending. D.G. DeNardo reports grants from the NIH/NCI during the conduct of the study. S.A. Stewart reports grants from the National Institute on Aging, the NCI (CA217208 and P30CA091842), the American Cancer Society, the Department of Defense, and Centene during the conduct of the study; a patent for methods for predicting cancer patient outcome and determining cancer treatment based on p38 gene signature pending; and that p38 inhibitor chow was provided free of charge from Aclaris. No disclosures were reported by the other authors.
Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies. SIGNIFICANCE: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design.
AB - Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies. SIGNIFICANCE: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design.
UR - http://www.scopus.com/inward/record.url?scp=85160970196&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-22-0907
DO - 10.1158/2159-8290.CD-22-0907
M3 - Article
C2 - 36883955
AN - SCOPUS:85160970196
SN - 2159-8274
VL - 13
SP - 1454
EP - 1477
JO - Cancer discovery
JF - Cancer discovery
IS - 6
ER -