Reprogramming the Tumor Microenvironment in Desmoplastic Tumors to Potentiate Cancer Immunotherapy

Abstract

In recent years, immunotherapy has achieved unprecedented success in the clinic, especially in melanoma, kidney, bladder, head and neck, renal, and lung cancers. However, similar outcomes have yet to be achieved in metastatic breast cancer (mBC). This is likely in part due to the presence of an immunosuppressive tumor microenvironment (TME), driven by a highly desmoplastic stroma in mBC. For my dissertation, I explored strategies to re-engineer the desmoplastic TME to overcome therapeutic resistance to immune checkpoint blockade (ICB), and developed an approach to identify predictive biomarkers of responsiveness to ICB. First, we developed a novel TME-activated polymeric material that can be conjugated with a class of anti-hypertensive drugs to target tumor desmoplasia, enhance anti-tumor activity of T-lymphocytes, and prolong animal survival when combined with ICB in mouse models of mBC. Next, we investigated the effects of targeting CXCR4/CXCL12 signaling, a prominent tumor-promoting axis that governs stromal cell interactions and cancer metastasis. We found that silencing of CXCR4 expression in CAFs significantly halted the development of spontaneous lung metastases. In addition, pharmacological inhibition of CXCR4 reduced desmoplasia and immunosuppression in the metastatic TME. Lastly, using a mouse model of BC, we developed a novel approach to identify TME biomarkers that differentiate responders from non-responders to ICB. In summary, the desmoplastic and immunosuppressive breast TME impedes effective outcomes of ICB. Reprogramming the TME using stromal-targeting agents could enhance ICB therapy in mBC. Additionally, elucidating predictive biomarkers will provide valuable insights for designing the optimal therapeutic strategies for mBC patients.