Nat Med: Poor response to advanced kidney cancer immunotherapy revealed

Renal transparent cell cancer (ccRCC, the most common kidney cancer) is one of the most common malignancies in the urinary systemImmunocheckpoint inhibitor drugs currently used to treat advanced kidney cancer, such as Keytruda and Opdivo, can enhance the immune response to kidney cancer cells by blocking PD-1In 2018, immunotherapy became a popular research topic for renal cell cancer therapy after Navuliu monoto-anti-combination ipimonolite became the standard first-line program for advanced renal transparent cell carcinomaIn early 2019, the results of the clinical phase III trial of Paboli Singantis And Aviru MUPA-Axitinib were published in the New England Journal of MedicineThe two immune checkpoint inhibitors combined targeted drug regimens, in their respective clinical trials, showed significant efficacy over the first-line standard program, sunitinibIn April 2019, Paboli Zuma Singaitin received FDA and EU approval for first-line treatment of advanced renal cell carcinomaAdvanced kidney cancer usually does not respond to standard chemotherapy, and PD-1 checkpoint inhibitors provide a powerful new weapon for the treatment of advanced kidney cancerIn cancers such as melanoma and lung cancer, checkpoint inhibitors are more effective against tumors with a "high mutation load", i.ewith more DNA mutationsIn contrast, although the number of mutations in advanced renal transparent cell carcinoma is moderate, the response to checkpoint inhibitors is relatively limited, and researchers do not know whyIn addition, another inexplicable difference is that in melanoma and some other cancers, tumors are soaked in large numbers of immunoCD8 T cells, creating an inflammatory or "hot" environment within the tumor, which provides a better response to PD-1 blockingHowever, in advanced renal cancer, the high immersion of CD8 T cells was associated with poor prognosisAfter analyzing tumors in patients with advanced kidney cancer treated with immunotherapy in three clinical trials, researchers at dana-Farber Cancer Institute identified several characteristics that can affect the response of kidney tumors to immunocheckpoint inhibitorsThe study was presented at the Clinical Science Symposium at the Annual Meeting of the American Society of Clinical Oncology (ASCO) and also published in Nature MedicinePhoto Source: Nature Medicine Scientists say the study provides important clues about the genetics of kidney cancer and the interactions between genetics and the immune system, which may be crucial in predicting which patients are likely to benefit from immunotherapy drugsImmunotherapy drugs have been approved for first- and second-line treatment of kidney cancer, but not for all patients In this study, those characteristics, which are usually associated with immunotherapy responses or drug resistance in other types of cancer, did not perform well in advanced renal transparent cell carcinoma The researchers analyzed 592 tumors collected from patients with advanced kidney cancer who had participated in clinical trials of PD-1 blocking drugs, using all exosome groups and RNA sequencing to reveal genomic changes in tumors and other factors associated with how patienttumors respond edited the drug To determine which characteristics of advanced renal cancer cells are associated with responses or tolerancetos to PD-1 inhibitors, when analyzing tumors in these patients, researchers looked for biomarkers that might be associated with the patient's prognosis (e.g., no progression survival and total survival), such as genetic changes, mutations, copy number changes, etc in the kidney cancer cell genome The most interesting thing found in the study, said Dr David Braun, the paper's first author, that, unlike other types of tumors, some of the characteristics of kidney tumors did not affect the response to PD-1 inhibitordrugs For example, in general, tumors that contain a large number of new antigens from cancer-related DNA mutations may make the tumor's response to immunotherapy stronger, but not for kidney tumors In addition, even if kidney tumors are deeply immersed in CD8 immune T cells (which in other types of cancer sedituate with a strong immune attack on the tumor), there is virtually no difference in prognosis in these kidney cancer patients "In kidney cancer, immunological 'hot' tumors don't respond better than 'cold' tumors, which is a surprising result," Braun said The ABILITY OF HLA molecules to present antigens to the immune system, which are individual-specific, is another factor affecting the response of some cancer types, but also does not affect the immune response of late-stage kidney tumors "We were also very surprised, " said Dr Catherine Wu, the paper's author We previously assumed that the presentation and response potential of the patient's immune system to more antigens might be related to a better prognosis, but it is clear that kidney cancer is not suitable for this standard model Somatic cell variability and HLA purity are not related to the clinical prognosis of PD-1 blocking (Photo: Nature Medicine) However, there are some factors that explain this unexpected observation Late-stage renal tumors are deeply immersed in CD8 T cells, and although they are immunological "hot" tumors, their response to immunocheckpoint inhibitors is not strong After a comprehensive analysis of the genome changes in kidney tumors, the researchers found that the lack of a mutation in the kidney tumor PBRM1 gene, which is associated with PD-1 blocking therapy can improve survival, and kidney tumors also have a large number of 9p21.3 chromosome fragments missing, and the deletion of this fragment is associated with PD-1 blocking adverse prognosis Lead researcher Dr Sachet Shukla explained: "We think these two factors may explain why CD8 T-cell immersion did not cause tumorresponses for checkpoint blocker therapy, while in other cancer types that showed CD8 T-cell immersion but did not have the above chromosome changes, there was an immune response." Dr Sabina Signoretti, lead researcher on anti-PD-1 treatment response and drug resistance and genome-related correlation (Photo: Nature Medicine) Lead researcher and Professor of Pathology at Harvard Medical School, believes these findings suggest that the interaction between immune T-cell immersion and tumor DNA changes, such as the inactivation of the PBRM1 gene and the abundance of 9p21.3 deficiency, may be an important factor in tumor response to PD-1 blocking, perhaps in renal cancer The same is true in other types of tumors
"This study provides important insights into the immune genome mechanisms that lead to immune response and tolerance in renal transparent cell carcinoma," concluded Professor Toni Choueiri of Harvard Medical School, co-author of the paper on the potential interaction of immune immersion and genomic profiling of tumors in PD-1 blocking responses (Photo: Nature Medicine) Detailed clinical, genomic, transcriptological and immunopathological data will also provide valuable resources for the field of cancer immunology Therefore, this work is critical to ongoing research on precision medicine and immuno-oncology, to help identify which patients may respond to current therapies, and to provide the basis for the future development of sound combination therapies to overcome drug resistance "