Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced ...tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms.
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•Anti-PD-1 and anti-CTLA-4 utilize distinct cellular mechanisms•T cell responses to different tumor models are fundamentally similar•Anti-PD-1 and anti-CTLA-4 both target subsets of exhausted-like CD8 T cells•CTLA-4 blockade induces expansion of ICOS+ Th1-like CD4 T cells
Anti-CTLA-4 and anti-PD-1 checkpoint-blockade therapies target distinct tumor-infiltrating T cell populations to induce tumor rejection.
Metastases are responsible for the majority of cancer-related deaths. Although genomic heterogeneity within primary tumors is associated with relapse, heterogeneity among treatment-naïve metastases ...has not been comprehensively assessed. We analyzed sequencing data for 76 untreated metastases from 20 patients and inferred cancer phylogenies for breast, colorectal, endometrial, gastric, lung, melanoma, pancreatic, and prostate cancers. We found that within individual patients, a large majority of driver gene mutations are common to all metastases. Further analysis revealed that the driver gene mutations that were not shared by all metastases are unlikely to have functional consequences. A mathematical model of tumor evolution and metastasis formation provides an explanation for the observed driver gene homogeneity. Thus, single biopsies capture most of the functionally important mutations in metastases and therefore provide essential information for therapeutic decision-making.
Clinical reports of limited and treatable cancer metastases, a disease state that exists in a transitional zone between localized and widespread systemic disease, were noted on occasion historically ...and are now termed oligometastasis. The ramification of a diagnosis of oligometastasis is a change in treatment paradigm, i.e. if the primary cancer site (if still present) is controlled, or resected, and the metastatic sites are ablated (surgically or with radiation), a prolonged disease-free interval, and perhaps even cure, may be achieved. Contemporary molecular diagnostics are edging closer to being able to determine where an individual metastatic deposit is within the continuum of malignancy. Preclinical models are on the outset of laying the groundwork for understanding the oligometastatic state. Meanwhile, in the clinic, patients are increasingly being designated as having oligometastatic disease and being treated owing to improved diagnostic imaging, novel treatment options with the potential to provide either direct or bridging therapy, and progressively broad definitions of oligometastasis.
Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular ...analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.
Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the ...prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined.
The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic ...approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
Recent pre-clinical and clinical research has provided evidence that cancer progression is driven not only by a tumour's underlying genetic alterations and paracrine interactions within the tumour ...microenvironment, but also by complex systemic processes. We review these emerging paradigms of cancer pathophysiology and discuss how a clearer understanding of systemic regulation of cancer progression could guide development of new therapeutic modalities and efforts to prevent disease relapse following initial diagnosis and treatment.
Most cancer-associated deaths occur due to metastasis, yet our understanding of metastasis as an evolving, heterogeneous, systemic disease and of how to effectively treat it is still emerging. ...Metastasis requires the acquisition of a succession of traits to disseminate, variably enter and exit dormancy, and colonize distant organs. The success of these events is driven by clonal selection, the potential of metastatic cells to dynamically transition into distinct states, and their ability to co-opt the immune environment. Here, we review the main principles of metastasis and highlight emerging opportunities to develop more effective therapies for metastatic cancer.
Metastasis is the most lethal manifestation of cancer, but our understanding of its biology and how to effectively treat it is rapidly advancing. This review highlights established and emerging principles of metastasis and provides a framework to develop more effective therapies for metastatic cancer.
Oligometastasis: Past, Present, Future Gutiontov, Stanley I; Pitroda, Sean P; Weichselbaum, Ralph R
International journal of radiation oncology, biology, physics,
11/2020, Volume:
108, Issue:
3
Journal Article
Peer reviewed
In this review, we discuss the oligometastatic state, with a focus on its current and future relevance within the field of radiation therapy. We first outline the scope of the problem and the ...evolving understanding of metastatic disease existing along a spectrum. We then transition to a discussion of the clinical data that led to the formulation of the oligometastatic hypothesis, delving in some detail into the clinical factors associated with improved outcomes in the setting of local therapy-whether surgical or radiotherapeutic. In particular, we highlight the marked limitations of using clinical criteria alone to determine the absence or presence of true extracranial oligometastatic disease. After this, we briefly discuss the radiation therapy literature that has recently demonstrated benefits in cancer-specific outcomes with ablative treatment of oligometastatic disease. We emphasize data in the setting of non-small cell lung cancer and prostate cancer and briefly discuss the importance of our enhanced ability to detect occult metastatic disease with improved imaging technologies. After noting that resulted and ongoing prospective trials of ablative radiation therapy use the most rudimentary of oligometastatic classifiers-number of metastases-as their inclusion criteria, we transition to our core argument: a growing body of preclinical and translational work aims to refine the definition of oligometastatic disease using molecular features. We address genomic, epigenetic, and immunologic features that have, across histology, demonstrated an improved ability to prognosticate when combined with classic clinical correlates of oligometastatic disease. We also discuss studies that suggest particular molecular targets which, when manipulated for therapeutic purposes, have the potential to revert the polymetastatic phenotype to the oligometastatic one. We conclude with what we believe are the repercussions of this work for radiation therapy trials and clinical practice, and the importance of enriching and supporting these inquiries for the future of our field.
Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are ...genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
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