Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Here, we present a novel therapeutic approach to slow down PDAC cancer progression by targeting neutrophils.

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Neutrophils are the most abundant immune cell type in the PDAC microenvironment and recent advances in understanding neutrophil biology, have illuminated the role of neutrophils in cancer. Specific therapies targeting tumor-associated neutrophils are lacking despite progress in the research area. 

Neutrophil granulocytes arrive quickly to a site of infection and neutralize the threat to make way for other immune cells that participate in the rebuilding of the infected tissue. But their role seems to be inverted in pancreatic cancer, and they promote rather than fight tumor progression. Cancer cells can release factors into the blood stream that increase release of immature neutrophils from the bone marrow. These immature neutrophils promote cancer cell growth and metastasis in our PDAC model. 

We investigated how factors released from PDAC cancer cells activate signaling pathways in neutrophils. Our analyses suggested that the Pfizer FDA-approved drug lorlatinib, could be used as an inhibitor to block FES signaling, which we found was activated in the neutrophil granulocytes by the cancer cells.

We demonstrated that treatment with lorlatinib reduces the production and release of neutrophil granulocytes from the bone marrow, which leads to reduced infiltration in pancreatic tumors. As a result of this reduced neutrophil granulocytes infiltration, the primary- and metastatic- tumor burden was reduced in our models.

Schematic showing our tumour and metastatic model. (A) Cancer cells are injected in to the pancreas and the tumour is establishes over 14 days. From day 14 daily treatment with lorlatinib ensues resulting in a significant reduction in tumour weight (B). (C) Cancer cells are injected into the spleen where they will drain to the liver and form metastasis. (D) Mice treated with lorlatinib has a significantly reduced metastatic burden. 

Pancreatic cancer is a “cold” cancer type, meaning that immune therapy is not an effective treatment option due to the reduced number of T-cells in the tumor, and the suppression of cytotoxicity of the few T-cells close to the cancer cells. We discovered that when combining lorlatinib with anti PD-1 treatment, we could increase the efficacy of the immune check point blockade, making the “cold” pancreatic tumor “hot”. The T-cells regained some of their cytotoxic function and we additionally observed an increase in the number of T-cells with the combination therapy. The combination treatment was able to decrease the tumor burden further than lorlatinib alone. 
We have also confirmed our findings in a pre-clinical model of colon cancer and expect the findings to be relevant to other solid types of cancers. 

Our study has uncovered a way to specifically target tumor-associated neutrophils, which has great therapeutic potential as neutrophils are known to promote the progression of many cancer types.

We hope that our results can extend pancreatic cancer patient lives and since lorlatinib is already FDA approved treatment could be applied quickly to human patients.

Jan Strøbech

PhD student, University of Copenhagen