Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor–positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.
Programmed cell death-1 (PD-1) is an inhibitory receptor and plays an important role in the regulation of ab T cells. Little is known, however, about the role of PD-1 in cd T cells. In this study, we investigated the expression and function of PD-1 in human cd T cells. Expression of PD-1 was rapidly induced in primary cd T cells following antigenic stimulation, and the PD-1 1 cd T cells produced IL-2. When PD-1 1 cd T cells were stimulated with Daudi cells with and without programmed cell death ligand-1 (PD-L1) expression, the levels of IFN-c production and cytotoxicity in response to PD-L1 1 Daudi cells were diminished compared to the levels seen in response to PD-L1 À Daudi cells. The attenuated effector functions were reversed by anti-PD-L1 mAb. When PD-1 1 cd T cells were challenged by PD-L1 1 tumors pretreated with zoledronate (Zol), which induced cd TCR-mediated signaling, the resulting reduction in cytokine production was only slight to moderate compared to the reduction seen when PD-1 1 cd T cells were challenged by PD-L1 À tumors. In addition, cytotoxic activity of PD-1 1 cd T cells against Zol-treated PD-L1 1 tumors was comparable to that against Zol-treated PD-L1 À tumors. These results suggest that TCR triggering may partially overcome the inhibitory effect of PD-1 in cd T cells.Keywords: cd T cells . Phosphoantigen . PD-1 . PD-L1 . Tumor Supporting Information available online IntroductionHuman Vg2Jg1.2Vd2 (also termed Vg9JPVd2)-bearing gd T cells recognize the so-called phosphoantigens, a group consisting of isopentenyl pyrophosphate (IPP) and related metabolites derived from microbial pathogens in a gd TCR-dependent manner [1][2][3][4]. One of the most potent naturally occurring phosphoantigens is (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMB-PP), which is derived from the 2-C-methy-D-erythritol-4-phosphate/ 1-deoxy-D-xylulose-5-phosphate pathway, an isoprenoid-biosynthetic pathway unique to certain microbes and plants [5,6]; we and others have previously reported that the subset of gd T cells [7,8]. A growing body of evidence shows that N-BPs inhibit farnesyl pyrophosphate synthase downstream of IPP in the mammalian mevalonate pathway [9,10]. It has been suggested that the resulting intracellular accumulation of IPP in the tumor cells allows gd T cells to recognize the tumor cells [11,12], although the exact mechanisms whereby this may occur remain to be identified. An increase in intracellular IPP may also occur spontaneously in certain tumor cells [13,14]. Based on these results, it has been proposed that gd T cells may be involved in surveillance for cellular metabolic stress [15,16]. Activated gd T cells produce various cytokines including IFN-g and TNF-a and also exhibit potent cytotoxic activity [17,18], and thus may serve as potential effector cells against tumors [19]. The membrane protein known as programmed cell death-1 (PD-1) is a member of the immunoglobulin superfamily, which is induced in ab T cells following antigenic stimulation [20]. Upon engagement with its specific ligan...
Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a riskmanagement framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC.
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