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Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models
Amaia Martinez-Usatorre1,2, Ece Kadioglu1, Gael Boivin1,2
1Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), 1015 Lausanne, Switzerland.
Abstract:
Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of Kras G12D/+;p53 -/- NSCLC, including a mismatch repair-deficient variant (Kras G12D/+;p53 -/-;Msh2 -/-) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1+ regulatory T cells (Tregs), which were more efficiently targeted by the PD-1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor-β-rich tumor microenvironment that supported PD-1+ Tregs Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated Tregs, redirected the PD-1 antibody to CD8+ T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors.
Insights
Combining antiangiogenic therapy with immune checkpoint blockade (ICB) in lung cancer can fail. Targeting tumor-associated macrophages (TAMs) with CSF1R inhibitors and cisplatin re-sensitizes tumors to ICB, improving outcomes.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint blockade (ICB) using PD-1/PD-L1 antibodies shows limited efficacy in non-small cell lung cancer (NSCLC).
- Combination therapies involving chemotherapy or antiangiogenic drugs are explored to enhance ICB effectiveness in preclinical and clinical settings.
Purpose of the Study:
- To investigate the response and resistance mechanisms to combined ICB, antiangiogenic therapy, and chemotherapy in genetically engineered mouse models of NSCLC.
- To evaluate strategies for overcoming resistance to combination immunotherapies in NSCLC.
Main Methods:
- Utilized genetically engineered mouse models of KrasG12D/+;p53-/- NSCLC, including a mismatch repair-deficient variant.
- Administered combinations of anti-VEGF/angiopoietin-2, PD-1/PD-L1 antibodies, chemotherapy (cisplatin), and CSF1R inhibitors.
- Employed longitudinal imaging to monitor tumor progression and response; analyzed immune cell infiltration and tumor microenvironment components.
Main Results:
- Antiangiogenic therapy alone slowed tumor progression but combining it with ICB accelerated progression in some tumors.
- Antiangiogenic treatment increased PD-1+ regulatory T cells (Tregs) infiltration, which were preferentially targeted by PD-1 antibodies over CD8+ T cells.
- Dual targeting of tumor-associated macrophages (TAMs) with CSF1R inhibitors and cisplatin reduced Tregs, redirected PD-1 antibodies to CD8+ T cells, and enhanced antiangiogenic immunotherapy efficacy, leading to tumor regression.
Conclusions:
- The combination of antiangiogenic therapy and ICB can be ineffective or detrimental in NSCLC due to Treg-mediated immunosuppression.
- Targeting TAMs is crucial for overcoming resistance to antiangiogenic immunotherapy in NSCLC.
- Dual TAM inhibition combined with antiangiogenic therapy and ICB represents a promising strategy for improving NSCLC treatment outcomes.
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