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Surgery has contributed to unveil a tumor behavior that is difficult to reconcile with the models of tumorigenesis based on gradualism. The postsurgical patterns of progression include unexpected features such as distant interactions and variable rhythms. The underlying evidence can be summarized as follows: (1) the resection of the primary tumor is able to accelerate the evolution of micrometastasis in early stages, and (2) the outcome is transiently opposed in advanced tumors. The objective of this paper is to give some insight into tumorigenesis and surgery-related effects, by applying the concepts of the evolutionary theory in those tumor behaviors that gompertzian and tissular-centered models are unable to explain. According to this view, tumors are the consequence of natural selection operating at the somatic level, which is the basic mechanism of tumorigenesis, notwithstanding the complementary role of the intrinsic constrictions of complex networks. A tumor is a complicated phenomenon that entails growth, evolution and development simultaneously. So, an evo-devo perspective can explain how and why tumor subclones are able to translate competition from a metabolic level into neoangiogenesis and the immune response. The paper proposes that distant interactions are an extension of the ecological events at the local level. This notion explains the evolutionary basis for tumor dormancy, and warns against the teleological view of tumorigenesis as a process directed towards the maximization of a concrete trait such as aggressiveness. [ABSTRACT FROM AUTHOR]

Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. The growing interest over the past two decades in harnessing the immune system to eradicate cancer has been accompanied by heightened efforts to characterize cytokines and exploit their vast signaling networks to develop cancer treatments. The goal of this paper is to review the major cytokines involved in cancer immunotherapy and discuss their basic biology and clinical applications. The paper will also describe new cytokines in pre-clinical development, combinations of biological agents, novel delivery mechanisms, and potential directions for future investigation using cytokines. [ABSTRACT FROM AUTHOR]

Simple Summary: Ablation techniques use extremely hot or cold temperatures to kill small cancers. It is now known that in addition to killing the cancer cells, the ablation treatment may stimulate an immune response in patients against the cancer cells, acting like a vaccine. As a result, there is now interest in combining ablation together with drugs that target the immune system of patients with cancer to enhance the effects of both treatments. In order to develop such combined treatments and test them in clinical trials, we need to understand more about their effects so trials can be optimally designed to be most effective. We have analysed 164 circulating proteins in the blood from patients with small renal tumours undergoing ablation treatment to understand more about the effects of ablation on the patient, both at the level of the effects on the cancer cells and the response of the patients. Further biological understanding of the immune and inflammatory responses following ablation is critical to the rational development of combination ablation-immunotherapies. Our pilot exploratory study evaluated the circulating plasma protein profiles after image-guided ablation (IGA) of small renal masses to determine the resultant systemic effects and provide insight into impact both on the tumour and immune system. Patients undergoing cryotherapy (CRYO), radiofrequency ablation (RFA) or microwave ablation (MWA) for small renal tumours were recruited. Blood samples were obtained at four timepoints; two baselines prior to IGA and at 24 h and 1–3 months post-IGA, and a panel of 164 proteins measured. Of 55 patients recruited, 35 underwent ablation (25 CRYO, 8 RFA, 2 MWA) and biomarker measurements. The most marked changes were 24 h post-CRYO, with 29 proteins increasing and 18 decreasing significantly, principally cytokines and proteins involved in regulating inflammation, danger-associated molecular patterns (DAMPs), cell proliferation, hypoxic response, apoptosis and migration. Intra-individual variation was low but inter-individual variation was apparent, for example all patients showed increases in IL-6 (1.7 to 29-fold) but only 50% in CD27. Functional annotation analysis highlighted immune/inflammation and cell proliferation/angiogenesis-related clusters, with interaction networks around IL-6, IL-10, VEGF-A and several chemokines. Increases in IL-8, IL-6, and CCL23 correlated with cryoprobe number (p = 0.01, rs = 0.546; p = 0.009, rs = 0.5515; p = 0.005, rs = 0.5873, respectively). This initial data provide further insights into ablation-induced biological changes of relevance in informing trial design of immunotherapies combined with ablation. [ABSTRACT FROM AUTHOR]

Simple Summary: In light of expanding incidences of keratinocyte carcinoma (KC) with many patients developing multiple tumors, the demand for new treatment modalities is high. With the approval of cemplimab for locally advanced and metastasizing basal cell carcinoma and squamous cell carcinoma, KC is now included as an indication for systemic immunotherapy. At present, however, systemic KC therapy remains limited by the severe side effects associated with treatment. Immunotherapy might be more broadly applied if locally administered. Localized to the skin, KCs are easily accessible to topical drugs and physical interventions such as laser. There is an increasing appreciation of lasers' potential to activate an immune response. Further enhancement of the laser-based immune activation might be obtained by combining laser and immunotherapeutic agents, known as laser immunotherapy. In search of new treatment modalities for KC and aiming to broaden the field of KC immunotherapy, this review discusses the current literature on immune activation following both laser monotherapy and laser immunotherapy. The role of the immune system in cancer growth is well recognized and the development of immunotherapy represents a breakthrough in cancer treatment. Recently, the use of systemic immunotherapy was extended to keratinocyte carcinoma (KC), specifically locally advanced and metastasizing basal and squamous cell carcinoma. However, since most KC lesions are non-aggressive, systemic treatment with associated side effects is rarely justified. Conversely, topical immunotherapy with imiquimod remains restricted to premalignant and superficial lesions. Use of laser in the treatment of KC has evolved from physical tumor destruction and laser-assisted drug delivery to laser-mediated immune modulation. Evidence indicates that laser monotherapy can lead to immune cell infiltration, tumor reduction and resistance to tumor re-inoculation. Combining laser with immunotherapeutic agents, termed laser immunotherapy (LIT), may further potentiate immune activation and tumor response. Studies on LIT show not only direct anti-tumor effects but systemic adaptive immunity, illustrated by the prevention of tumor recurrence and regression in distant untreated tumors. These findings imply a therapeutic potential for both local and metastatic disease. This work provides rationales for immune-based treatment of KC and presents the current status of KC immunotherapy. Aiming to expand the field of KC immunotherapy, the review discusses the literature on immune activation following laser monotherapy and LIT. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastasis in general represents the progression phenotype whereby cancer cells break from a malignant primary location and travel to and invade other distant organs. Theoretically, tumor cells that exit the primary tumor might be eliminated by immune cells. The immune system has the ability to recognize and eliminate malignant tumor cells; however, failed immune surveillance contributes to cancer development. Disseminated tumor cells persist and reemerge as a clinically symptomatic disease. How do disseminated tumor cells evade immune surveillance? In this context, tumor/immune system interactions play a key role and are the subject of intense scrutiny. After colonization, the immunosuppressive tumor microenvironments of metastatic lesions promote tumor growth and worsen prognosis. Here, we discuss scientific advances relating to the interaction between disseminated tumor cells and the immune cells in tissue-specific tumor microenvironments. Most cancer-related deaths are a consequence of metastases, a series of linear events, notably the invasion–metastasis cascade. The current understanding of cancer immune surveillance derives from studies in primary tumors, but disseminated cancer cells acquire mutations and, in some cases, appear to progress independently after spreading from primary sites. An early step in this process is micrometastatic dissemination. As such, the equilibrium between the immune system and disseminated cancer cells controls the fate of the cancer. Immune checkpoint inhibitors (ICIs) exhibit significant clinical activity in patients, but the efficacy of ICIs depends on both the tumor and its microenvironment. Data often suggest that disseminated cancer cells are not adequately targeted by the immune system. In this review, we summarize the main basic findings of immune responses against disseminated tumor cells and their organ-specific characteristics. Such studies may provide new directions for cancer immune therapy. [ABSTRACT FROM AUTHOR]

All-trans retinoic acid (ATRA), a recognized differentiating agent, has significant potential in the personalized/stratified treatment of breast cancer. The present study reports on the molecular mechanisms underlying the anti-tumor activity of ATRA in breast cancer. The work is based on transcriptomic experiments performed on ATRA-treated breast cancer cell-lines, short-term tissue cultures of patient-derived mammary-tumors and a xenograft model. ATRA upregulates gene networks involved in interferon-responses, immune-modulation and antigen-presentation in retinoid-sensitive cells and tumors characterized by poor immunogenicity. ATRA-dependent upregulation of these gene networks is caused by a viral mimicry process, involving the activation of endogenous retroviruses. ATRA induces a non-canonical type of viral mimicry, which results in increased expression of the IRF1 (Interferon Responsive Factor 1) transcription factor and the DTX3L (Deltex-E3-Ubiquitin-Ligase-3L) downstream effector. Functional knockdown studies indicate that IRF1 and DTX3L are part of a negative feedback loop controlling ATRA-dependent growth inhibition of breast cancer cells. The study is of relevance from a clinical/therapeutic perspective. In fact, ATRA stimulates processes controlling the sensitivity to immuno-modulatory drugs, such as immune-checkpoint-inhibitors. This suggests that ATRA and immunotherapeutic agents represent rational combinations for the personalized treatment of breast cancer. Remarkably, ATRA-sensitivity seems to be relatively high in immune-cold mammary tumors, which are generally resistant to immunotherapy. [ABSTRACT FROM AUTHOR]