Nat Med: Study reveals factors that influence immune outcomes for kidney cancer
Last Update: 2020-06-17
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, June 10, 2020 /PRNewswire/ -- Scientists at theBiovalleyBIOON /-- By analyzing tumors in patients with advanced kidney cancer who received immunotherapy in threeclinical trials, scientists have identified severaltumorcharacteristics that affect their response to immunocheckpoint inhibitor drugsthe study was presented at the annual meeting of the American Society
for ClinicalOncology (ASCO) and was also published in the journal Nature MedicineThe researchers say the study provides important clues to thegeneticof kidney cancer and its interactions with the immune system and may prove critical to our ability to predict which patients may or will not be able to benefit from immunotherapy drugs that have been approved for first- and second-line treatmentsThis study showed that in other types of cancer, characteristics associated with immunotherapy responses or drug resistance did not play the same role in advanced transparent cell nephrocell cell carcinoma (ccRCC)Photo Source: Nature Medicine
"Kidney cancer breaks all these rules," said David Braun, M.D., an expert on kidney cancer at Dana Farber and the first author of the reporttransparent cell kidney cell cancer is the most common type of kidney cancer In the United States, there are about 74,000 new cases of kidney cancer and about 15,000 deaths each year Checkpoint inhibitor immunotherapy drugs such as pembrolizumab (Keytruda) and nivolumab (Opdivo) are used for advanced kidney cancer, which play a role by blocking PD-1 PD-1 is a protein in immune T cells that usually prevents these cells from attacking other cells in the body By blocking PD-1, these drugs can enhance the immune response to kidney cancer cells PD-1 checkpoint inhibitors bring a powerful new weapon against advanced kidney cancer, which often does not respond to standard chemotherapy In cancers such as melanoma and lung cancer, checkpoint inhibitors -- drugs such as pembrolizumab (Keytruda) and nivolumab (Opdivo), are often more effective for "high mutation burden" tumors, which means that their DNA is filled with many mutations By contrast, late-stage transparent cell renal cell carcinoma has only a moderate number of mutations, but is relatively sensitive to checkpoint inhibitors -- and scientists don't know why Another confusing difference is that in melanoma and some other cancers, tumors are soaked in large numbers of immune CD8 T cells, forming so-called inflammatory or "hot" environments within the tumor , and better respond to PD-1 blocking But in advanced renal cancer, the opposite is true -- high immersion of CD8 T cells is associated with poor prognosis in the study, scientists analyzed tumors in 592 patients with advanced kidney cancer who were involved in clinical trials of PD-1 blocking drugs
They used whole exosome groups and RNA sequencing, among other methods, to reveal genomic changes and other factors associated with patient
tumor response to the drug, especially patient's progression-free and overall survival the purpose of this study is to determine which characteristics of advanced kidney cancer cells are related to their response to PD-1 inhibitors or resistance In analyzing tumor in patients with advanced ccRCC treated with PD-1 inhibitors, the researchers looked at the genome of kidney cancer cells for biomarkers that might be related to the patient's prognostic survival and total survival, such as changes in genetic , mutations, and copy numbers Braun says some of the most interesting findings are the characteristics of kidney tumors, which, unlike other types of cancer, do not affect the response to PD-1 inhibitor drugs For example, tumors with large amounts of new antigens -- proteins produced by cancer-related DNA mutations -- may make tumors more sensitive to immunotherapy, but this has been incorrect in kidney tumors In addition, although kidney tumors are severely immersed in CD8 immune T cells -- which causes other types of cancer to have a strong immune attack on the tumor -- this does not actually lead to any difference in the prognosis of these kidney cancer patients "To our surprise, the immune system's 'hot' tumors do not respond as well as 'cold' tumors , " Braun said "
another factor affecting the responsiveness of certain cancers is that individuals who provide antigens to the immune system genetic specific HLA molecules do not affect the immune response of of late-stage kidney tumors "We were surprised," said Dr Wu, head of the 's stem cell transplant and cell therapy department "We reasonably assume that the patient's immune system's response to primary diversity may be related to a better prognosis, but kidney cancer clearly does not meet the standard pattern "
, however, we did find some factors that might explain these unexpected observations," said Dr Sachet A Shukla, head of the computational team at Dana-Farber Translational Translational Immunogenomics Laboratory, a genomics laboratory The study found that advanced kidney tumors that were severely immersed in CD8 T cells did not respond well to immunocheckpoint blockers, even if they were immune "hot" tumors The scientists analyzed changes in the genome of kidney cancer and found that the removal of mutated genes from the PBRM1 gene in tumors was associated with improved survival after PD-1 treatment, while the removal of chromosome fragments called 9p21.3 was associated with poor prognosis of PD-1 inhibitors Shukla explained: "We think these two factors may explain why cd8 T-cells in tumor do not cause them to respond to checkpoint blocker therapy, while other types of cancer, while showing CD8 T-cell immersion, do not have those chromosome changes Picture Source: "Our work underscores the importance of integrating genomic data and immunopathological data, which have been painstakingly studied by professional pathologists," said Dr Signoretti, a professor of pathology at Harvard Medical School.
"Our findings suggest that interaction stomosis between immune T-cells and tumor DNA mutations may have important implications for the response of tumor to PD-1 inhibitors, and may not only be applicable to renal cell carcinoma "
" current research provides important insights into the immune genome mechanisms that lead to the response and resistance of transparent cell nephroblastic immunotherapy," said Dr Chouey, director of the Lank Center for Urology And Professor of Medicine at Harvard Medical School Jerome and Nancy Kohlberg Detailed clinical, genomic, transcriptological and immunopathological data for this study will provide valuable resources for the cancer immunology community Therefore, this work is important for ongoing research on precision medicine and immunology oncology to help determine which patients may respond to current treatments and to provide basic information to help develop rational combination therapies to overcome drug resistance in the future "
" a noteworthy thing," says Choueiri, "is a collaboration between multiple disciplines and stakeholders: immunology , pathology, genetic , computing, and clinical expertise focus on a oncology , involving both academic and industry stakeholders." " (BioValleyBioon.com) References: Study reveals factors: study son of the students in the kidney cancer treated with thee
fared d-Va., D.A., Hou, Y., Bakouny, Z et al.
Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma.
Nature Medicine (2020) doi.org/10.1038/s41591-020-0839-y
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