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 patients with melanoma. 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 ICB is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.
Highlights
Immune-checkpoint blockade (ICB) with antibodies blocking CTLA-4 or PD-1 has received FDA approval for multiple solid tumor types [1]
carbonic anhydrase IX (CAIX) expression is an independent biomarker of worse overall survival in melanoma To determine whether CAIX expression at the protein level played a role in malignant melanoma, we stained a tissue microarray (TMA) comprised of 449 patient tumor samples for CAIX expression [31]
CAIX expression was detected across all melanoma subtypes contained within the TMA, expression was predominantly associated with cases that were metastatic and did not contain information on subtype classification of the primary lesion (Fig. 1B)
Summary
Immune-checkpoint blockade (ICB) with antibodies blocking CTLA-4 or PD-1 has received FDA approval for multiple solid tumor types [1]. Considerable response rates have been achieved in a subset of patients with metastatic melanoma [2, 3] and, to a lesser degree, patients with triple-negative breast cancer 4, 5) when treated with ICB alone. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). Current address for S.P. Shah: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
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