Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model

Abstract

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.

Expression and Clinical Significance of Lactate Dehydrogenase A in Colon Adenocarcinoma

“…As in COAD immunotherapy, the combined therapy of nivolumab/lpilimumab can effectively control the progression of microsatellite instability-high COAD (47); triptolide can suppress the infiltration of macrophages in the TME and participate in the regulation of tumor cell growth and apoptosis of COAD (48); romidepsin can promote the expression of PD-L1 in COAD, and change the state of anti-tumor immune responses in vivo (49). Recent studies showed that LDHA may be served as a therapeutic target of cancer immunotherapy (50,51). Oya et al (50) found that the function of LDHA was similar to PD-L1 in the immunotherapy of non-small cell lung cancer (NSCLC).…”

“…The patients with high LDHA expression levels indicated the poor efficacy of nivolumab in the treatment of NSCLC, and had shorter OS and progression free survival (PFS). Meanhwile, Qiao et al (51) demonstrated that in the NSCLC humanized mouse model, the LDHA inhibitor Oxamate could addictively enhance the efficacy of pembrolizumab that is an anti-PD-1 immunotherapy agent. Furthermore, GO analysis revealed that LDHA expression was also correlated with the immune system process to a certain extent (Figure 4B), suggesting that LDHA, as a novel target, has great prospect in the field of tumor immunotherapy.…”

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

“…To investigate the role of oxamate alone or in combination with pembrolizumab in the treatment of NSCLC, a PBMC-humanized mouse model was established. This model showed, while oxamate or pembrolizumab alone delayed tumor growth, their combination to be more efficient ( 95 ) ( Figure 2A ). This study successfully used humanized mice to demonstrate that new combination therapies can improve responsiveness to immunotherapy.…”

Microenvironmental influences on T cell immunity in cancer and inflammation

“…Importantly, when these lactate-targeting treatments did improve outcomes, multiple studies showed this to be a CTL-dependent effect and treatment with LDH shRNA synergized with PD-1 ICB yet failed to improve tumor outcomes in immunodeficient systems [ 157 ]. Supporting this notion, LDH inhibition controlled tumor growth in a preclinical humanized non-small cell lung cancer model in a CD8 + T cell dependent manner [ 160 ]. It was recently shown that preconditioning CTLs with LDH-A inhibition resulted in less terminally differentiated CTLs upon IL-2 treatment, while treatment with IL-21 did not alter cellular metabolism but did decrease transcription of LAG3, PD-1, and TIM3, leading to an overall increase in cell persistence, tumor control, and host survival [ 161 ].…”