RESUMO
PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with a significant challenge to effectively manage in the clinic worldwide. Immunotherapy may be beneficial to TNBC patients if responders can be effectively identified. Here we sought to elucidate the immune landscape of TNBCs by stratifying patients into immune-specific subtypes (immunotypes) to decipher the molecular and cellular presentations and signaling events of this heterogeneous disease and associating them with their clinical outcomes and potential treatment options. EXPERIMENTAL DESIGN: We profiled 730 immune genes in 88 retrospective Indian TNBC samples using the NanoString platform, established immunotypes using non-negative matrix factorization-based machine learning approach, and validated them using Western TNBCs (n=422; public datasets). Immunotype-specific gene signatures were associated with clinicopathological features, immune cell types, biological pathways, acute/chronic inflammatory responses, and immunogenic cell death processes. Responses to different immunotherapies associated with TNBC immunotypes were assessed using cross-cancer comparison to melanoma (n=504). Tumor-infiltrating lymphocytes (TILs) and pan-macrophage spatial marker expression were evaluated. RESULTS: We identified three robust transcriptome-based immunotypes in both Indian and Western TNBCs in similar proportions. Immunotype-1 tumors, mainly representing well-known claudin-low and immunomodulatory subgroups, harbored dense TIL infiltrates and T-helper-1 (Th1) response profiles associated with smaller tumors, pre-menopausal status, and a better prognosis. They displayed a cascade of events, including acute inflammation, damage-associated molecular patterns, T-cell receptor-related and chemokine-specific signaling, antigen presentation, and viral-mimicry pathways. On the other hand, immunotype-2 was enriched for Th2/Th17 responses, CD4+ regulatory cells, basal-like/mesenchymal immunotypes, and an intermediate prognosis. In contrast to the two T-cell enriched immunotypes, immunotype-3 patients expressed innate immune genes/proteins, including those representing myeloid infiltrations (validated by spatial immunohistochemistry), and had poor survival. Remarkably, a cross-cancer comparison analysis revealed the association of immunotype-1 with responses to anti-PD-L1 and MAGEA3 immunotherapies. CONCLUSION: Overall, the TNBC immunotypes identified in TNBCs reveal different prognoses, immune infiltrations, signaling, acute/chronic inflammation leading to immunogenic cell death of cancer cells, and potentially distinct responses to immunotherapies. The overlap in immune characteristics in Indian and Western TNBCs suggests similar efficiency of immunotherapy in both populations if strategies to select patients according to immunotypes can be further optimized and implemented.
RESUMO
BACKGROUND: A number of epidemiologic studies of Parkinson 's disease (PD) have been conducted worldwide over the years. Although every study reported the rise in prevalence and incidence rate of PD with the increasing age, the overall estimates were different across countries. The variation in reported data may partly be contributed by case ascertainment, case finding method, data collection, and most importantly different population structures. OBJECTIVE: Systematically review prevalence and incidence of PD and find the causes of variation in the results. MATERIAL AND METHOD: A literature search was conducted on Medline and EMBASE for studies worldwide investigating the prevalence and incidence of PD and included all adults, English and publication between 1965 and January 2010. The primary search of both databases yielded 5,330 results. After screening topics and abstracts, 168 relevant abstracts were tagged and saved for more thorough perusal. Ultimately, 40 papers were selected for review after applying the pre-specified inclusion criteria RESULTS: The worldwide prevalence of PD varies widely. One reason for the variation in prevalence estimates could be due to the differences in survival across countries. The use of epidemiological studies using medical records could be another reason for the variation in disease frequency. CONCLUSION: PD is common in the elderly. A number of descriptive epidemiologic studies have been conducted worldwide. Comparing the incidence and prevalence of Parkinson's disease is difficult.
