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Cancer Immunol Res. 2019 May 14. pii: canimm.0657.2018. doi: 10.1158/2326-6066.CIR-18-0657. [Epub ahead of print]

Targeting hypoxia-induced carbonic anhydrase IX enhances immune checkpoint blockade locally and systemically.

Author information

1
Integrative Oncology, British Columbia Cancer Research Centre.
2
Molecular Oncology, British Columbia Cancer Research Centre.
3
Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre.
4
Pathology and Laboratory Medicine, University of British Columbia.
5
Department of Molecular Oncology, British Columbia Cancer Research Centre.
6
Integrative Oncology, BC Cancer Research Centre.
7
Department of Molecular Oncology, British Columbia Cancer Agency.
8
Dermatology and Skin Science, University of British Columbia.
9
Molecular Oncology, British Columbia Cancer Agency.
10
Department of Biochemistry & Molecular Biology, BC Cancer Research Centre sdedhar@bccrc.ca.

Abstract

Treatment strategies involving immune checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 melanoma patients. We found that targeting CAIX with the small molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of CA9 is associated with a reduced Th1 response in metastatic melanoma and basal-like breast cancer TCGA cohorts. These data suggest that targeting CAIX in the TME in combination with immune checkpoint blockade is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.

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