Wonkyung Oh, A. Kim, D. Dhawan, D. Knapp, Seung-Oe Lim
{"title":"肿瘤细胞源性乳酸抑制PD-L1蛋白和PD-L1抗体在PD-L1/PD-1阻断治疗耐药肿瘤中的相互作用","authors":"Wonkyung Oh, A. Kim, D. Dhawan, D. Knapp, Seung-Oe Lim","doi":"10.1101/2023.08.04.551990","DOIUrl":null,"url":null,"abstract":"Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. Nontheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. The findings in this study provide a new mechanism of how lactic acid induces an immunosuppressive environment and suggest a potential combination treatment to overcome the PD-1/PD-L1 blockade therapy resistance.","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"5 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2023-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tumor cell-derived lactic acid inhibits the interaction of PD-L1 protein and PD-L1 antibody in the PD-L1/PD-1 blockade therapy-resistant tumor\",\"authors\":\"Wonkyung Oh, A. Kim, D. Dhawan, D. Knapp, Seung-Oe Lim\",\"doi\":\"10.1101/2023.08.04.551990\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. Nontheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. The findings in this study provide a new mechanism of how lactic acid induces an immunosuppressive environment and suggest a potential combination treatment to overcome the PD-1/PD-L1 blockade therapy resistance.\",\"PeriodicalId\":72407,\"journal\":{\"name\":\"bioRxiv : the preprint server for biology\",\"volume\":\"5 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv : the preprint server for biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2023.08.04.551990\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv : the preprint server for biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2023.08.04.551990","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Tumor cell-derived lactic acid inhibits the interaction of PD-L1 protein and PD-L1 antibody in the PD-L1/PD-1 blockade therapy-resistant tumor
Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. Nontheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. The findings in this study provide a new mechanism of how lactic acid induces an immunosuppressive environment and suggest a potential combination treatment to overcome the PD-1/PD-L1 blockade therapy resistance.