p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy

Abstract

Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKa inhibition (p38i) limits tumor growth by reprograming the metastatic tumor microenvironment in a CD4+ T cell, IFNy, 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 anti-metastatic therapies.

Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis

“…Given that bone is a frequent metastasis site for breast cancer, we performed intratibial injection of 3-month-old female Malat1 +/+ , Malat1 −/− , and Malat1 −/− ; Malat1 Tg/Tg mice with the EO771 cell line, a cell line derived from a mouse mammary tumor on a C57BL/6 background 38 . Before injecting tumor cells, we conducted μCT scanning and confirmed that at this age, only female Malat1 −/− mice, but not female Malat1 +/+ and Malat1 −/− ; Malat1 Tg/Tg mice, exhibited signs of osteoporosis (Supplementary Fig.…”

Promoting longevity with less cancer: The 2022 International Conference on Aging and Cancer

“…43 Her laboratory utilized a stromal-labeling approach and single-cell RNA sequencing to identify targets that increased p38i efficacy and found that p38i and an OX40 agonist can synergistically reduce metastatic growth and increase overall survival. 43 The combination of p38i, anti-OX40, and cytotoxic T cell engagement cured mice of metastatic disease and produced long-term immunologic memory. 43 Their findings suggest that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies.…”

“…43 The combination of p38i, anti-OX40, and cytotoxic T cell engagement cured mice of metastatic disease and produced long-term immunologic memory. 43 Their findings suggest that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies.…”

“…Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. Dr. Stewart's recent work showed that p38MAPKa inhibition (p38i) limits tumor growth by reprograming the metastatic tumor microenvironment in a CD4+ T cell, IFNy, and macrophage‐dependent manner 43 . Her laboratory utilized a stromal‐labeling approach and single‐cell RNA sequencing to identify targets that increased p38i efficacy and found that p38i and an OX40 agonist can synergistically reduce metastatic growth and increase overall survival 43 .…”

“…Dr. Stewart's recent work showed that p38MAPKa inhibition (p38i) limits tumor growth by reprograming the metastatic tumor microenvironment in a CD4+ T cell, IFNy, and macrophage‐dependent manner 43 . Her laboratory utilized a stromal‐labeling approach and single‐cell RNA sequencing to identify targets that increased p38i efficacy and found that p38i and an OX40 agonist can synergistically reduce metastatic growth and increase overall survival 43 . The combination of p38i, anti‐OX40, and cytotoxic T cell engagement cured mice of metastatic disease and produced long‐term immunologic memory 43 .…”