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Key Points A thorough review of the literature on interferon (IFN) use in cancer, using breast cancer as a case study, with discussion of the few clinical studies with sufficient numbers and sufficiently robust design to draw any conclusions. The clinical successes of IFNs (in other cancers) are often in blood-borne cancers and/or the setting of low tumour burden. New understanding of the immune response to tumours and its regulation by the different types of IFN provides exciting opportunities for redesigning when and how IFNs can be used in the clinic. IFNs are produced by various cell types in the tumour microenvironment, where they can have direct effects on tumour cells or indirect effects via modulation of the immune response. Technology-driven improvements in measuring IFN responses via transcriptomics (and potentially proteomics) provides insights into the signal transduction pathways activated or inactivated during tumorigenesis. They also provide 'signatures' that can indicate the potential responsivity of patients to particular forms of therapy, including IFN. A telling example is the discovery that tumour-cell-derived, IRF7-driven, type I IFN activates the immune system to target the process of metastasis. This paves the way for the use of IFN therapy in an adjuvant setting. There are indications requiring further study that IFN may work well in combination with other immune-based therapies (for example, checkpoint inhibitors that target the programmed cell death protein PD1 or its ligand, PDL1) or hormonal therapies for which synergistic effects might be expected because components of partner pathways are themselves IFN regulated. Interferons (IFNs) activate and regulate antitumour immune responses. This Review discusses lessons that can be learnt from using type I IFNs in oncology and our current understanding of the interferome in modifying antitumour immune responses. The interferons (IFNs) are a family of cytokines that protect against disease by direct effects on target cells and by activating immune responses. The production and actions of IFNs are finely tuned to achieve maximal protection and avoid the potential toxicity associated with excessive responses. IFNs are back in the spotlight owing to mounting evidence that is reshaping how we can exploit this pathway therapeutically. As IFNs can be produced by, and act on, both tumour cells and immune cells, understanding this reciprocal interaction will enable the development of improved single-agent or combination therapies that exploit IFN pathways and new 'omics'-based biomarkers to indicate responsive patients.

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings. Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.

Key Points Metastasis is the major cause of morbidity for patients with breast cancer, as few curative therapies are available. To develop more effective treatments, a better understanding of metastasis and the genes that regulate the process is necessary. Owing to early tumour cell dissemination before primary tumour diagnosis, target genes need to be identified that have a functional role in metastatic progression after tumour cell entry into the circulation. Current therapies that target the primary tumour may not necessarily target disseminated tumour cells or subsequent metastases. The use of circulating tumour cells to predict and monitor patient response to therapies may be important for improving individualized therapeutics. There are two general ways of identifying metastasis-associated genes as potential therapeutic targets. Human gene expression profiling or tissue arrays of primary tumours, disseminated tumour cells and metastases can be used to find genes whose expression correlates with clinical parameters such as disease-free survival. Assessment of a functional role in the process can be achieved using appropriate animal models of metastatic disease. Alternatively, metastasis-regulating genes can be identified using mouse models and subsequently verified as being relevant in human breast cancer by analysing transcript or protein levels in tissue samples. Approximately 20% of the patients who are diagnosed with breast cancer will subsequently develop metastatic disease. Challenges exist in identifying the patients for whom adjuvant chemotherapy is required. Testing the efficacy of current and emerging therapeutics against disseminated tumour cells in the adjuvant setting is of crucial importance for the future. Metastasis is the main cause of mortality for patients with cancer. For the development of more effective treatments, a better understanding of the mechanisms of metastasis is required. In this Review, Anderson and colleagues discuss the processes underlying metastasis in breast cancer and describe how advances in the identification of relevant signalling pathways and genetic regulators can facilitate the development of novel targeted anti-metastatic drugs. Nearly all deaths caused by solid cancers occur as a result of metastasis — the formation of secondary tumours in distant organs such as the lungs, liver, brain and bone. A major obstruction to the development of drugs with anti-metastatic efficacy is our fragmented understanding of how tumours 'evolve' and metastasize, at both the biological and genetic levels. Furthermore, although there is significant overlap in the metastatic process among different types of cancer, there are also marked differences in the propensity to metastasize, the extent of metastasis, the sites to which the tumour metastasizes, the kinetics of the process and the mechanisms involved. Here, we consider the case of breast cancer, which has some marked distinguishing features compared with other types of cancer. Considerable progress has been made in the development of preclinical models and in the identification of relevant signalling pathways and genetic regulators of metastatic breast cancer, and we discuss how these might facilitate the development of novel targeted anti-metastatic drugs.

The authors identify Irf7 and associated interferon signaling as an important factor suppressing bone metastasis of breast cancers. Irf7 is lost in experimental metastasis and human bone metastastic tissue, and this fosters an immunosuppressive environment that facilitates metastasis. Manipulating this innate immune signaling pathway emerging from tumor cells by interferon administration had beneficial effects in mouse models by reducing bone metastasis and increasing survival time. Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8 + T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis–free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.

Cancers evade the immune system through the process of cancer immunoediting. While immune checkpoint inhibitors are effective for reactivating tumour immunity in some cancer types, many other solid cancers, including breast cancer, remain largely non-responsive. Understanding how non-responsive cancers evade immunity and whether this occurs at the clonal level will improve immunotherapeutic design. Here we use DNA barcoding to track murine mammary cancer cell clones during immunoediting and determine clonal transcriptional profiles that allow immune evasion following anti-PD1 plus anti-CTLA4 immunotherapy. Clonal diversity is significantly restricted by immunotherapy treatment in both primary tumours and metastases, demonstrating selection for pre-existing breast cancer cell populations and ongoing immunoediting during metastasis and treatment. Immunotherapy resistant clones express a common gene signature associated with poor survival of basal-like breast cancer patient cohorts. At least one of these genes has an existing small molecule that can potentially be used to improve immunotherapy response. Understanding the molecular mechanisms of cancer immunoediting could provide insight into resistance to immunotherapy. Here, DNA barcoding provides evidence of ongoing immunoediting during metastasis and treatment with anti-PD1 and anti-CTLA4, and identifies cancer cell clones with unique immune evasive phenotypes.

Mammographic screening has led to increased detection of breast cancer at a pre-invasive state, hence modelling the earliest stages of breast cancer invasion is important in defining candidate biomarkers to predict risk of relapse. Discrimination of pre-invasive from invasive lesions is critically important for such studies. Myoepithelial cells are the barrier between epithelial cells and the surrounding stroma in the breast ductal system. A number of myoepithelial immunohistochemistry markers have been identified and validated in human tissue for use by pathologists as diagnostic tools to distinguish in situ carcinoma from invasive breast cancer. However, robust myoepithelial markers for mouse mammary tissue have been largely under-utilised. Here, we investigated the utility of the myoepithelial markers smooth muscle actin (SMA), smooth muscle myosin heavy chain (SMMHC), cytokeratin-14 (CK14) and p63 to discriminate mammary intraepithelial neoplasia (MIN) from invasive disease in the C57BL/6J MMTV-PyMT transgenic model of mammary carcinoma. We identified that SMMHC and CK14 are retained in early in situ neoplasia and are appropriate markers for distinguishing MIN from invasive disease in this model. Additionally, the proliferation marker Ki67 is a superior marker for differentiating between normal and hyperplastic ducts, prior to the development of MIN. Based on this, we developed a scoring matrix for discriminating normal, hyperplasia, MIN and invasive lesions in this spontaneous mammary tumorigenesis model. This study demonstrates heterogeneous expression of myoepithelial proteins throughout tumour development, and highlights the need to characterise the most appropriate markers in other models of early breast cancer to allow accurate classification of disease state.

Lutetium-177 [177Lu]Lu-PSMA-I&T (177Lu-PSMA-I&T) and the bone-seeking α-emitter radium-223 (223Ra) are established life-extending therapies for patients with metastatic castration-resistant prostate cancer; however, resistance and progression are inevitable. We aimed to evaluate the safety and preliminary antitumour activity of 177Lu-PSMA-I&T combined with 223Ra in this patient group. We conducted an investigator-initiated, single-centre, single-arm, phase 1/2 trial (AlphaBet) at the Peter MacCallum Cancer Centre in Melbourne, Australia. Adults (aged ≥18 years) with a diagnosis of progressive, metastatic castration-resistant prostate cancer, an Eastern Cooperative Oncology Group performance status score of 0–2, at least two visible bone metastases not treated with radiotherapy, previous exposure to an androgen receptor pathway inhibitor, prostate-specific membrane antigen (PSMA)-positive disease (defined by maximum standardised uptake value ≥20 at a site of disease), and no discordant sites (ie, avid on 2-[18F]fluoro-2-deoxy-D-glucose-PET–CT with minimal PSMA expression and no uptake on bone scintigraphy) were eligible for inclusion. Phase 1 dose-escalation assessed two dose levels of 223Ra (27·5 kBq/kg and 55·0 kBq/kg) combined with 7·4 GBq 177Lu-PSMA-I&T, administered intravenously every 6 weeks for up to six cycles. Phase 2 dose expansion continued with the recommended phase 2 dose. Co-primary endpoints were the maximum tolerated or administered dose and the recommended phase 2 dose (phase 1), and the PSA response rate (phase 2), analysed in all patients treated at the maximum tolerated or administered dose in either phase. Safety was assessed in all patients who received at least one dose of either protocol treatment in phase 1 or 2. Herein, we report the results of an interim analysis, which was added to the protocol following an amendment on May 30, 2024. This trial is registered at ClinicalTrials.gov (NCT05383079) and follow-up is ongoing. Between Nov 3, 2022, and Nov 5, 2024, 37 patients were enrolled, of whom 36 (97%; median age 72·5 years [IQR 67·0–78·0]) were included in the safety analysis and 33 (89%) were included in the preliminary activity analysis. No dose-limiting toxicities were observed. The recommended phase 2 dose of 223Ra was 55·0 KBq/kg combined with 7·4 GBq 177Lu-PSMA-I&T, administered every 6 weeks. With a median follow-up of 13·3 months (IQR 8·7–17·1), 11 (31%) patients completed all six cycles of both treatments. 18 (50%) patients discontinued treatment early, primarily due to unequivocal disease progression (11 [61%]) or adverse events (three [17%]). A reduction in PSA of at least 50% was observed in 18 (55%; 95% CI 36–72) patients. Grade 3 or higher treatment-related adverse events occurred in five (14%) of 36 patients, including anaemia (four [11%]) and neutropenia (three [8%]), with no treatment-related deaths. Non-clinically significant grade 3 lymphopenia occurred in ten (28%) patients. The combination of 177Lu-PSMA-I&T and 223Ra is safe and feasible in patients with metastatic castration-resistant prostate cancer and bone metastases. These findings warrant further evaluation of combined α-emitting and β-emitting approaches. Prostate Cancer Foundation, Bayer, and National Health and Medical Research Council.

Background Current therapies fail to cure over a third of osteosarcoma patients and around three quarters of those with metastatic disease. “Smac mimetics” (also known as “IAP antagonists”) are a new class of anti-cancer agents. Previous work revealed that cells from murine osteosarcomas were efficiently sensitized by physiologically achievable concentrations of some Smac mimetics (including GDC-0152 and LCL161) to killing by the inflammatory cytokine TNFα in vitro, but survived exposure to Smac mimetics as sole agents. Methods Nude mice were subcutaneously or intramuscularly implanted with luciferase-expressing murine 1029H or human KRIB osteosarcoma cells. The impacts of treatment with GDC-0152, LCL161 and/or doxorubicin were assessed by caliper measurements, bioluminescence, 18 FDG-PET and MRI imaging, and by weighing resected tumors at the experimental endpoint. Metastatic burden was examined by quantitative PCR, through amplification of a region of the luciferase gene from lung DNA. ATP levels in treated and untreated osteosarcoma cells were compared to assess in vitro sensitivity. Immunophenotyping of cells within treated and untreated tumors was performed by flow cytometry, and TNFα levels in blood and tumors were measured using cytokine bead arrays. Results Treatment with GDC-0152 or LCL161 suppressed the growth of subcutaneously or intramuscularly implanted osteosarcomas. In both models, co-treatment with doxorubicin and Smac mimetics impeded average osteosarcoma growth to a greater extent than either drug alone, although these differences were not statistically significant. Co-treatments were also more toxic. Co-treatment with LCL161 and doxorubicin was particularly effective in the KRIB intramuscular model, impeding primary tumor growth and delaying or preventing metastasis. Although the Smac mimetics were effective in vivo, in vitro they only efficiently killed osteosarcoma cells when TNFα was supplied. Implanted tumors contained high levels of TNFα, produced by infiltrating immune cells. Spontaneous osteosarcomas that arose in genetically-engineered immunocompetent mice also contained abundant TNFα. Conclusions These data imply that Smac mimetics can cooperate with TNFα secreted by tumor-associated immune cells to kill osteosarcoma cells in vivo. Smac mimetics may therefore benefit osteosarcoma patients whose tumors contain Smac mimetic-responsive cancer cells and TNFα-producing infiltrating cells.

Metastasis, the spread of cancer from a primary site to distant organs, is an important challenge in oncology. This Review explores the complexities of immune escape mechanisms used throughout the metastatic cascade to promote tumor cell dissemination and affect organotropism. Specifically, we focus on adaptive plasticity of disseminated epithelial tumor cells to understand how they undergo phenotypic transitions to survive microenvironmental conditions encountered during metastasis. The interaction of tumor cells and their microenvironment is analyzed, highlighting the local and systemic effects that innate and adaptive immune systems have in shaping an immunosuppressive milieu to foster aggressive metastatic tumors. Effectively managing metastatic disease demands a multipronged approach to target the parallel and sequential mechanisms that suppress anti-tumor immunity. This management necessitates a deep understanding of the complex interplay between tumor cells, their microenvironment and immune responses that we provide with this Review. This Review on the interplay between the immune system and metastasis is part of our wider Series of Reviews on Cancer Immunology and Immunotherapy.