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Therapeutic irradiation of the tumor microenvironment causes differential activation of pro-survival and pro-death pathways in malignant, stromal, endothelial and immune cells, hence causing a profound cellular and biological reconfiguration via multiple, non-redundant mechanisms. Such mechanisms include the selective elimination of particularly radiosensitive cell types and consequent loss of specific cellular functions, the local release of cytokines and danger signals by dying radiosensitive cells, and altered cytokine secretion by surviving radioresistant cells. Altogether, these processes create chemotactic and immunomodulatory cues for incoming and resident immune cells. Here we discuss how cytoprotective and cytotoxic signaling modules activated by radiation in specific cell populations reshape the immunological tumor microenvironment. Radiation therapy has for decades been a standard form of treatment for many cancers. A Review by Galluzzi and colleagues explores the effects of radiation therapy in the context of the immune response.

Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.

Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development. Immunotherapeutic interventions might be effective tools for the treatment of hepatocellular carcinoma. This Review provides up-to-date information on the clinical use of currently available immunotherapies in hepatocellular carcinoma, the mechanisms of response and resistance, and the therapeutic strategies under development. Key points Multiple immune mechanisms are important in the development and progression of hepatocellular carcinoma (HCC) and correlate with prognosis. Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable and clinically beneficial against advanced HCC. At present, the best available first-line treatment for advanced HCC is a combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab. There is as yet an almost complete lack of suitable biomarkers to guide the development of checkpoint inhibitors and their combinations in HCC. Immunotherapy is likely to synergize with local and locoregional interventions in earlier stages of HCC. Other promising forms of immunotherapy for HCC such as additional checkpoint inhibitors, adoptive cell transfer, vaccination and virotherapy are being actively pursued.

Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future design of novel combination therapies.

Populations facing lethal environmental change can escape extinction through rapid genetic adaptation, a process known as evolutionary rescue. Despite extensive study, evolutionary rescue is largely unexplored in mutualistic communities, where it is likely constrained by the less adaptable partner. Here, we explored empirically the likelihood, population dynamics, and genetic mechanisms underpinning evolutionary rescue in an obligate mutualism involving cross-feeding of amino acids between auxotrophic Escherichia coli strains. We found that over 80% of populations overcame a severe decline when exposed to two distinct types of abrupt, lethal stress. Of note, in all cases only one of the strains survived by metabolically bypassing the auxotrophy. Crucially, the mutualistic consortium exhibited greater sensitivity to both stressors than a prototrophic control strain, such that reversion to autonomy was sufficient to alleviate stress below lethal levels. This sensitivity was common across other stresses, suggesting it may be a general feature of amino acid–dependent obligate mutualisms. Our results reveal that evolutionary rescue may depend critically on the specific genetic and physiological details of the interacting partners, adding rich layers of complexity to the endeavor of predicting the fate of microbial communities facing intense environmental deterioration. Rapid genetic adaptation to environmental change, or evolutionary rescue, can be constrained by a less adaptable mutualistic partner. Here, the authors explore evolutionary rescue in an obligate mutualism between crossfeeding E. coli strains, finding that stress can lead to mutualism breakdown through the reversion to autonomy of one partner.

After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines. Brody and colleagues discuss the current status and potential of cancer vaccines, highlighting challenges and opportunities to advance promising candidates to the clinic.

Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients ( n  = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors. In a retrospective analysis of data from four phase 3 clinical trials, elevated baseline serum IL-8 levels were associated with worse clinical outcomes in patients with multiple tumor types treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combinatorial therapy.

Macrophage polarization is relevant for tumor biology. M2 polarized macrophages favor tumor growth and survival, while M1 macrophages support tumor destruction and antigen presentation. Markers identifying M1/M2 polarization are a subject of debate. We conducted a systematic review and meta-analysis to investigate the association of proposed macrophage markers with prognosis across epithelial tumors and melanoma. The Medline search engine was used and 195 articles were recovered for full review. Only articles which measured markers using immunohistochemistry or immunofluorescence and had overall survival (OS) as the primary endpoint were included. One hundred and thirteen articles were finally accepted for analysis. CD68 was associated with worse survival across tumors (hazard ratio (HR) = 1.24, 95% CI = 1.11–1.37). Tumor anatomical location influenced this association. Colorectal tumors showed an inverse association between CD68 and OS in contrast to the rest of cancer types (HR = 0.56 vs. 1.34). The approach taken to measure CD68 had an impact on prognosis; when macrophages were measured at the tumor invasion front prognosis was more favorable than when they were measured intratumorally (HR = 0.94 vs. 1.4). CD163, CD204, and CD206 showed a robust association with worse OS (HR = 1.63, 1.95, 1.65, respectively). Tumors arising in the lung and the liver showed a weaker association between CD163 and OS as compared with other locations ( β  = −0.5401 for the lung and −0.5940 for the liver compared with other anatomical locations). The counting strategy also had an impact on CD163 association with OS, with hot-spot counting having higher HRs compared with averaging macrophage counts across spots or absolute cell counting ( β  = −0.4678). In conclusion, proposed M2 markers are associated with worse survival across epithelial tumors and melanoma. The anatomical origin of tumors influences this association. The compartment where the macrophages were scored and counting strategy influenced the association with OS of CD68 and CD163, respectively.

Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival 1 , 2 . Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later. Neoadjuvant nivolumab treatment in patients with glioblastoma induces intratumoral immune activation and underscores the need for rationale-based combination approaches for improving clinical responses.

Key Points Clinical trials have validated immuno-oncology as a new pillar of anticancer therapy. Combinations could involve two (or more) sequential or simultaneous immunotherapies, and/or immunotherapies in combination with conventional cancer therapies. The programmed cell death protein 1 (PD1)–PD1 ligand 1 (PDL1) axis seems to be the most promising immuno-oncology target, and its blockade is likely to become the main foundation for combination strategies in the foreseeable future. The paradigm of immuno-oncology combinations is to block PD1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) simultaneously; this blockade is synergistic and shows clinical benefit in patients with melanoma but has an increased frequency of immune-mediated, albeit clinically manageable, toxic effects. Even if designing rational combinations that provide optimal benefit to patients with cancer is a challenging process, there are a number of different combination immuno-oncology therapies currently in development. Immunotherapy has undoubtedly become an effective treatment for many cancers, but how can we make the most of this approach? In this Review, Melero et al . discuss how immune-targeted therapies can be synergistically combined to provide maximal benefit to patients. Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients.