Hypoxia and anaerobic metabolism relate with immunologically cold breast cancer and poor prognosis

Purpose Hypoxia-Inducible Factor HIF1 alpha and lactate dehydrogenase LDHA drive anaerobic tumor metabolism and define clinical aggressiveness. We investigated their expression in breast cancer and their role in immune response and prognosis of breast cancer. Methods Tissue material from 175 breast cancer patients treated in a prospective study were analyzed with immunohistochemistry for HIF1 alpha and LDHS expression, in parallel with the tumor-infiltrating lymphocyte TIL-density and tertiary lymphoid structure TLS -density. Results High LDHS expression was noted in 48/175 tumors, and this was related to HIFla overexpression (p < 0.0001), triple-negative TNBC histology (p = 0.01), poor disease-specific survival (p < 0.007), metastasis (p < 0.01), and locoregional recurrence (p =0 .03). High HIF1 alpha expression, noted in 39/175 cases, was linked with low steroid receptor expression (p < 0.05), her2 overexpression (p = 0.01), poor survival (p < 0.04), and high metastasis rates (p < 0.004). High TIL-density in the invading tumor front (TILinv) was linked with low LDHS and HIF expression (p < 0.0001) and better prognosis (p < 0.02). High TIL-density in inner tumor areas (TILinn) was significantly linked with TNBC. Multivariate analysis showed that PgR-status (p = 0.003, HR 2.99, 95% CI 1.4-6.0), TILinv (p = 0.02, HR 2.31, 95% CI 1.1-4.8), LDHS (p =0 .01, HR 2.43, 95% CI 1.2-5.0), N-stage (p = 0.04, HR 2.42, 95% CI 1.0-5.8), T-stage (p = 0.04, HR 2.31, 95% CI 1.0-5.1), and her2 status (p = 0.05, HR 2.01, 95% CI 1.0-4.2) were independent variables defining death events. Conclusion Overexpression of LDHS, an event directly related to HIF1 alpha overexpression, characterizes a third of breast tumors, which is more frequent in TNBC. Both HIF1 alpha and LDHS define cold breast cancer microenvironment and poor prognosis. A rational is provided to study further whether metabolic manipulations targeting HIF and LDHS may enhance the antitumor immune response in breast cancer.