Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a fraction of patients show response to ICI, and there is an unmet need for ...biomarkers that will identify patients more likely to respond to ICI. Here we report that the ICI response prediction biomarker tumor mutational burden (TMB) shows significant sex differences. TMB's predictive power is significantly better for female than for male lung cancer patients. Receiver operating characteristic curve analysis was performed and the area under the curve (AUC) was reported to evaluate the predictive power of TMB in lung cancer ICI response. Hazard ratios (HR) of TMB‐high vs. TMB‐low patients were compared between male and female patients. Both AUC and HR differences between female and male are significant in all available independent lung cancer datasets. However, the AUC of programmed death ligand 1 (PD‐L1) expression does not show a difference between female and male, suggesting TMB, but not PD‐L1 expression has a better predictive power for female than for male lung cancer patients. Our study suggests significant sex differences in the performance of TMB in ICI response prediction. Future development of ICI biomarker should consider sex differences and special efforts should be paid to improve the performance of ICI predictive biomarkers for male lung cancer patients.
What's new?
Only a fraction of cancer patients show response to immune checkpoint inhibitors (ICI), and there remains an unmet need for biomarkers to select patients most likely to benefit. Inherent sex differences in immune response could potentially influence the performance of predictive biomarkers. Here, the authors report that the emerging biomarker tumor mutational burden (TMB) shows significant sex differences, with TMB's predictive power being significantly better for female than for male lung cancer patients. Future development of predictive biomarkers for ICI response should consider sex differences, and the performance of biomarkers for male lung cancer patients should also be improved.
Sex differences in innate and adaptive immune responses are known, and women generally mount a stronger immune response than men. Cancer immunotherapy, represented by immune checkpoint inhibitors ...(ICIs), has revolutionized the treatment of cancer, and sex differences in cancer immunotherapy are just starting to be revealed. Here, we summarize recent research progress concerning sex differences in cancer immunotherapy efficacy. On their own, ICIs tend to be more effective in male cancer patients compared with female patients, while ICIs combined with chemotherapy tend to be more effective in female patients than male patients. Male tumors are usually more antigenic than female tumors, and this is reflected by their increased number of tumor mutations and cancer germline antigens. The biomarker tumor mutational burden (TMB), which reflects tumor antigenicity, is more effective at predicting immunotherapy response for female lung cancer patients than for male patients. In this review, we propose different therapeutic strategies for the different sexes: For male cancer patients, the immune environment should be enhanced, whereas for female cancer patients, tumor antigenicity should be enhanced.
Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a small percentage of patients show response to ICI, and there is an unmet ...need for biomarkers that will identify patients who are more likely to respond to immunotherapy. The fundamental basis for ICI response is the immunogenicity of a tumor, which is primarily determined by tumor antigenicity and antigen presentation efficiency. Here, we propose a method to measure tumor immunogenicity score (TIGS), which combines tumor mutational burden (TMB) and an expression signature of the antigen processing and presenting machinery (APM). In both correlation with pan-cancer ICI objective response rates (ORR) and ICI clinical response prediction for individual patients, TIGS consistently showed improved performance compared to TMB and other known prediction biomarkers for ICI response. This study suggests that TIGS is an effective tumor-inherent biomarker for ICI-response prediction.
Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have ...been extensively studied in different types of cancer. Copy number alterations are important drivers for the progression of multiple cancer. However, practical tools for studying the signatures of copy number alterations are still lacking. Here, a user-friendly open source bioinformatics tool "sigminer" has been constructed for copy number signature extraction, analysis and visualization. This tool has been applied in prostate cancer (PC), which is particularly driven by complex genome alterations. Five copy number signatures are identified from human PC genome with this tool. The underlying mutational processes for each copy number signature have been illustrated. Sample clustering based on copy number signature exposure reveals considerable heterogeneity of PC, and copy number signatures show improved PC clinical outcome association when compared with SBS signatures. This copy number signature analysis in PC provides distinct insight into the etiology of PC, and potential biomarkers for PC stratification and prognosis.
Free radical mediated alkylation of alkenes is a challenging and largely unmet goal. Disclosed here is a conceptually novel “polarity umpolung” strategy for radical alkylation of alkenes using a ...portfolio of easily accessed, difunctional alkylating reagents. This strategy is achieved by substituting inherently nucleophilic alkyl radicals with electrophilic sulfone‐bearing surrogates, thus inverting the usual mode of reactivity. Along with alkylation, either an heteroaryl or oximino group is concurrently incorporated into the alkenes by a consecutive docking and migration process, leading to valuable products. The reaction displays a broad functional‐group tolerance under mild reaction conditions. The protocol opens new vistas for the late‐stage modification of complex natural products and drug molecules containing alkene moieties.
Polarity switch: A novel, mild, easy‐to‐execute protocol for radical alkylation of alkenes was developed using a polarity umpolung strategy. Both activated and challenging unactivated alkenes are suitable substrates. The protocol opens new vistas for the late‐stage modification of complex natural products and drug molecules containing alkene moieties.
Neutrino oscillation is deemed as an interesting physical phenomenon and shows the nonclassical features made apparently by the Leggett–Garg inequality. The uncertainty principle is one of the ...fundamental features that distinguishes the quantum world to its classical counterpart. And the principle can be depicted in terms of entropy, which forms the so-called entropic uncertainty relations (EUR). In this work, the entropic uncertainty relations that are relevant to the neutrino-flavor states are investigated by comparing the experimental observation of neutrino oscillations to predictions. From two different neutrino sources, we analyze ensembles of reactor and accelerator neutrinos for different energies, including measurements performed by the Daya Bay collaboration using detectors at 0.5 and 1.6 km from their source, and by the MINOS collaboration using a detector with a 735km distance to the neutrino source. It is found that the entropy-based uncertainty conditions strengths exhibits non-monotonic evolutions as the energy increases. We also quantify the systemic quantumness measured by quantum correlation, and derive the intrinsic relationship between quantum correlation and EUR. Furthermore, we utilize EUR as a criterion to detect entanglement of neutrino-flavor state. Our results could illustrate the potential applications of neutrino oscillations on quantum information processing in the weak-interaction processes.
The aryl‐to‐vinyl nickel 1,4‐migration (1,4‐Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated ...brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4‐Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.
The 1,4‐nickel migration process from aryl to alkenyl groups is now reported for the first time. The alkenyl nickel intermediates generated by this highly stereoselective migration process can be coupled with brominated alkanes to form multisubstituted olefins. The current method provides a new and efficient approach for the synthesis of Z/E olefins with high stereoselectivity.
Neutrino oscillation is an important physical phenomenon in elementary particle physics, and its nonclassical features can be revealed by the Leggett–Garg inequality. It shows that its quantum ...coherence can be sustained over astrophysical length scales. In this work, we investigate the measure of quantumness in experimentally observed neutrino oscillations via the nonlocal advantage of quantum coherence (NAQC), quantum steering, and Bell nonlocality. From various neutrino sources, ensembles of reactor and accelerator neutrinos are analyzed at distinct energies, such as Daya Bay (0.5 km and 1.6 km) and MINOS (735 km) collaborations. The NAQC of two-flavor neutrino oscillation is characterized experimentally compared to the theoretical prediction. It exhibits non-monotonously evolutive phenomenon with the increase of energy. Furthermore, it is found that the NAQC is a stronger quantum correlation than quantum steering and Bell nonlocality even in the order of km. Hence, for an arbitrary bipartite neutrino-flavor state with achieving a NAQC, it must be also a steerable and Bell nonlocal state. The results might offer an insight into the neutrino oscillation for the further applications on quantum information processing.
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