Cancer cell-intrinsic mechanisms driving acquired immune tolerance

Immune evasion is a hallmark of cancer, enabling tumors to survive contact with the host immune system and evade the cycle of immune recognition and destruction. Here, we review the current understanding of the cancer cell-intrinsic factors driving immune evasion. We focus on T cells as key effectors of anti-cancer immunity and argue that cancer cells evade immune destruction by gaining control over pathways that usually serve to maintain physiological tolerance to self. Using this framework, we place recent mechanistic advances in the understanding of cancer immune evasion into broad categories of control over T cell localization, antigen recognition, and acquisition of optimal effector function. We discuss the redundancy in the pathways involved and identify knowledge gaps that must be overcome to better target immune evasion, including the need for better, routinely available tools that incorporate the growing understanding of evasion mechanisms to stratify patients for therapy and trials

Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications

Multiple subclonal populations of tumor cells can coexist within the same tumor. This intra-tumor heterogeneity will have clinical implications and it is therefore important to identify factors that drive or suppress such heterogeneous tumor progression. Evolutionary biology can provide important insights into this process. In particular, experimental evolution studies of microbial populations, which exist as clonal populations that can diversify into multiple subclones, have revealed important evolutionary processes driving heterogeneity within a population. There are transferrable lessons that can be learnt from these studies that will help us to understand the process of intra-tumor heterogeneity in the clinical setting. In this review, we summarize drivers of microbial diversity that have been identified, such as mutation rate and environmental influences, and discuss how knowledge gained from microbial experimental evolution studies may guide us to identify and understand important selective factors that promote intra-tumor heterogeneity. Furthermore, we discuss how these factors could be used to direct and optimize research efforts to improve patient care, focusing on therapeutic resistance. Finally, we emphasize the need for longitudinal studies to address the impact of these potential tumor heterogeneity-promoting factors on drug resistance, metastatic potential and clinical outcome

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

PMCID: PMC4636050.-- et al.Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis.We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.E.B. is a Rosetrees Trust fellow; M.J.H. has a Cancer Research UK fellowship; N.Mu. received funding from the Rosetrees Trust; M.G. is funded by the UK Medical Research Council; I.V. is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal; R.C.R. and D.M.R. are partly funded by the Cambridge Biomedical Research Centre and Cancer Research UK Cancer Centre; P.V.L. is a postdoctoral researcher of the Research Foundation—Flanders (FWO); S.M.J. is a Wellcome Senior Fellow in Clinical Science; and C.S. is a senior Cancer Research UK clinical research fellow and is funded by Cancer Research UK, the Rosetrees Trust, European Union Framework Programme 7 (projects PREDICT and RESPONSIFY, ID:259303), the Prostate Cancer Foundation, the European Research Council and the Breast Cancer Research Foundation. This research is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.Peer Reviewe

Insights into the metastatic cascade through research autopsies

Metastasis is a complex process and the leading cause of cancer-related death globally. Recent studies have demonstrated that genomic sequencing data from paired primary and metastatic tumours can be used to trace the evolutionary origins of cells responsible for metastasis. This approach has yielded new insights into the genomic alterations that engender metastatic potential, and the mechanisms by which cancer spreads. Given that the reliability of these approaches is contingent upon how representative the samples are of primary and metastatic tumour heterogeneity, we review insights from studies that have reconstructed the evolution of metastasis within the context of their cohorts and designs. We discuss the role of research autopsies in achieving the comprehensive sampling necessary to advance the current understanding of metastasis

The translational challenges of precision oncology

The translational challenges in the field of precision oncology are in part related to the biological complexity and diversity of this disease. Technological advances in genomics have facilitated large sequencing efforts and discoveries that have further supported this notion. In this review, we reflect on the impact of these discoveries on our understanding of several concepts: cancer initiation, cancer prevention, early detection, adjuvant therapy and minimal residual disease monitoring, cancer drug resistance, and cancer evolution in metastasis. We discuss key areas of focus for improving cancer outcomes, from biological insights to clinical application, and suggest where the development of these technologies will lead us. Finally, we discuss practical challenges to the wider adoption of molecular profiling in the clinic and the need for robust translational infrastructure

A Breast Cancer Meta-Analysis of Two Expression Measures of Chromosomal Instability Reveals a Relationship with Younger Age at Diagnosis and High Risk Histopathological Variables

Breast cancer in younger patients often presents with adverse histopathological features, including increased frequency of estrogen receptor negative and lymph node positive disease status. Chromosomal instability (CIN) is increasingly recognised as an important prognostic variable in solid tumours. In a breast cancer meta-analysis of 2423 patients we examine the relationship between clinicopathological parameters and two distinct chromosomal instability gene expression signatures in order to address whether younger age at diagnosis is associated with increased tumour genome instability. We find that CIN, assessed by the two independently derived CIN expression signatures, is significantly associated with increased tumour size, ER negative or HER2 positive disease, higher tumour grade and younger age at diagnosis in ER negative breast cancer. These data support the hypothesis that chromosomal instability may be a defining feature of breast cancer biology and clinical outcome