Locally sourced: site-specific immune barriers to metastasis | Nature Reviews Immunology
Locally sourced: site-specific immune barriers to metastasis | Nature Reviews Immunology
- Perspective
- Published:
Locally sourced: site-specific immune barriers to metastasis
Nature Reviews Immunology (2023)
Abstract
Tumour cells migrate very early from primary sites to distant sites, and yet metastases often take years to manifest themselves clinically or never even surface within a patient’s lifetime. This pause in cancer progression emphasizes the existence of barriers that constrain the growth of disseminated tumour cells (DTCs) at distant sites. Although the nature of these barriers to metastasis might include DTC-intrinsic traits, recent studies have established that the local microenvironment also controls the formation of metastases. In this Perspective, I discuss how site-specific differences of the immune system might be a major selective growth restraint on DTCs, and argue that harnessing tissue immunity will be essential for the next stage in immunotherapy development that reliably prevents the establishment of metastases.
Concluding remarks
The evidence presented herein provides a renewed endorsement of Paget’s seed and soil hypothesis, yet newly contextualized to tissue immunity. Driven by anatomical organization, immune cells are indexed to tissues at defined ratios and spatial locations, where they engage in dynamic interactions with non-immune resident cells to constantly safeguard tissue homeostasis. It is the product of these interactions that sets the immune tone for DTC recognition, and makes an ideal locale for DTCs to either establish metastases or be kept dormant. Mounting an efficient antimetastatic immune response requires tissue-resident immune cells to coordinate their individual activation into global tissue-level responses, a feat that can be achieved only by long-range intercellular communication, as mediated by soluble factors (such as cytokines and growth factors). Thus, a systematic quantitative framework to monitor the different cellular and soluble architects of antimetastatic immune responses, and how they intersect with DTC intrinsic traits and individual conditions, in each tissue, in space and time, will be needed to optimize the choice of interventional approach in patients at risk of developing metastases.
As we begin to appreciate site-specific antimetastatic immunity and its therapeutic potential, a few challenges and exciting opportunities lie ahead before we leverage DTC–immune cell biology into targeted immunotherapies (Box 2). The first challenge is to improve detection of DTCs and accurately assess metastatic dynamics in patients throughout treatment, which will be greatly facilitated by increased establishment of and access to rapid autopsy programmes. The second is to continue increasing our understanding of the spatiotemporal regulation of dormant and metastatic niches, so as to predict which patients are likely to develop metastases, and how to effectively manage site-specific metastatic disease across cancer types; here, orthogonal spatial technologies have been revolutionary, and it is anticipated that their widespread implementation, combined with improved computational approaches to analyse multiple large datasets, will bring resolution of the niche full circle. The third challenge is to develop preclinical models that can translate to human immunity, and thus guide rational combination therapy strategies in future clinical trials. Finally, these trials should be large and long enough to support the complexity of precision immuno-oncology protocols, and extend clinical end points beyond the traditional progression-free survival readout that appraises only metastases to also include DTC burden. Continued progress in overcoming these challenges demands a collective interdisciplinary effort to inform the next stage in immunotherapy development that will bring long-lasting cures for all patients across all cancer types.
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