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Published on: January 19, 2019
KRASG12D drives immunosuppression in lung adenocarcinoma through paracrine signaling
Emily L Lasse-Opsahl1, Ivana Barravecchia2,3,4, Elyse McLintock2,3
1Graduate Program in Cancer Biology.
Abstract:
Lung cancer is the leading cause of cancer deaths in the United States. New targeted therapies against the once-deemed undruggable oncogenic KRAS are changing current therapeutic paradigms. However, resistance to targeted KRAS inhibitors almost inevitably occurs; resistance can be driven by tumor cell-intrinsic changes or by changes in the microenvironment. Here, we utilized a genetically engineered mouse model of KRASG12D-driven lung cancer that allows for inducible and reversible expression of the oncogene: activation of oncogenic KRASG12D induces tumor growth; conversely, inactivation of KRASG12D causes tumor regression. We showed that in addition to regulating cancer cell growth and survival, oncogenic KRAS regulated the transcriptional status of cancer-associated fibroblasts and macrophages in this model. Utilizing ex vivo approaches, we showed that secreted factors from cancer cells induced the expression of multiple cytokines in lung fibroblasts, and in turn drove expression of immunosuppressive factors, such as arginase 1, in macrophages. In summary, fibroblasts emerged as a key source of immune regulatory signals, and a potential therapeutic target for improving the efficacy of KRAS inhibitors in lung cancer.
Insights
Targeted KRAS inhibitors show promise for lung cancer, but resistance is common. This study reveals how cancer-associated fibroblasts and macrophages in the tumor microenvironment contribute to resistance, offering new therapeutic targets.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Lung cancer remains a leading cause of cancer mortality.
- Targeted therapies for oncogenic KRAS mutations are emerging but face inevitable resistance.
- Resistance mechanisms can involve tumor-intrinsic changes or the tumor microenvironment.
Purpose of the Study:
- To investigate the role of the tumor microenvironment in resistance to KRAS inhibitors.
- To elucidate how oncogenic KRAS influences cancer-associated fibroblasts and macrophages.
- To identify potential therapeutic targets for overcoming KRAS inhibitor resistance.
Main Methods:
- Utilized a genetically engineered mouse model with inducible and reversible KRASG12D expression.
- Analyzed transcriptional changes in cancer-associated fibroblasts and macrophages.
- Employed ex vivo co-culture systems to study cell-cell interactions and secreted factors.
Main Results:
- Oncogenic KRAS regulates the transcriptional state of fibroblasts and macrophages.
- Cancer cell-secreted factors induce cytokine expression in fibroblasts.
- Fibroblast-derived signals promote immunosuppressive factor expression (e.g., arginase 1) in macrophages.
Conclusions:
- Cancer-associated fibroblasts are key regulators of the immune microenvironment in KRAS-driven lung cancer.
- Fibroblasts represent a potential therapeutic target to enhance KRAS inhibitor efficacy.
- Targeting the fibroblast-macrophage axis may overcome resistance to KRAS-targeted therapies.
