Abstract A013: Targeting perivascular macrophages with an orally bioavailable heme oxygenase-1 inhibitor improves responses to chemotherapeutic drugs in cancer
Authors: Bahri Meriem , Al-Adhami Taha , Demirel Emre , Anstee Joanne E. , Feehan Karen T. , Rosekilly James , Gillett Cheryl E. , Sosnowska Dominika , Gitsaki-Taylor Renee , Cheung Tik Shing , Spicer James F. , Rahman Khondaker Miraz , Arnold James N. 
Published: December 2023

Abstract
The tumor microenvironment (TME) plays a crucial role in cancer progression. It consists of various elements including stromal cells, proteins, and physical factors that support the growth and spread of cancer. Targeting the TME has become an appealing strategy for cancer treatment. Tumor-associated macrophages (TAMs) are an abundant stromal cell type in the TME and, due to their plasticity, TAMs can be exploited by cancer cells and the broader stromal reaction to promote a pro-tumoral response. TAMs have been implicated in facilitating a variety of pro-tumoral pathways including resistance to anti-cancer therapeutics, immune suppression, angiogenesis, and metastasis. Our group has recently characterized a subpopulation of pro-angiogenic and immune-suppressive TAMs which can be identified by their expression of the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). LYVE-1+ TAMs reside spatially proximal to blood vasculature and adopt a collaborative multi-cellular ‘nest’ arrangement which may support their biological activity. LYVE-1+ TAMs selectively express high levels of the immunomodulatory enzyme heme oxygenase-1 (HO-1), an enzyme which catabolizes heme to generate the biologically active catabolites carbon monoxide (CO), biliverdin and ferrous iron. Genetic inactivation of HO-1 in LYVE-1+ TAMs results in improved anti-tumoral CD8 T-cell responses and enhanced response to chemotherapy, resulting in prolonged tumor control in a spontaneous MMTV-PyMT murine model of breast cancer. Unfortunately, current HO-1 inhibitors are not orally bioavailable, which limits their utility as immunotherapeutics for the treatment of cancer. In response to this hurdle, we have developed a next generation HO-1 inhibitor called KCL-HO-1i. We demonstrate in pharmacokinetic studies that KCL-HO-1i is orally bioavailable in murine models with a serum half-life of around 3hours. Furthermore, orally delivering KCL-HO-1i alongside standard of care chemotherapy is able to deliver durable tumor control in MMTV-PyMT mice. We have characterized the response of the TME to KCL-HO-1i using flow cytometry, immunofluorescence and RNA sequencing approaches and demonstrate that KCL-HO-1i supports a broader switch from an immunological ‘cold’ to ‘hot’ TME which provides a more favourable immune landscape for improving the response to chemotherapeutic drugs. Taken together, our data support the use of KCL-HO-1i as novel immunotherapeutic for the treatment of cancer.
Citation Format: Meriem Bahri, Taha Al-Adhami, Emre Demirel, Joanne E. Anstee, Karen T. Feehan, James Rosekilly, Cheryl E. Gillett, Dominika Sosnowska, Renee Gitsaki-Taylor, Tik Shing Cheung, James F. Spicer, Khondaker Miraz Rahman, James N. Arnold. Targeting perivascular macrophages with an orally bioavailable heme oxygenase-1 inhibitor improves responses to chemotherapeutic drugs in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A013.