In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of “classic” ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.

Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21’s antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy.

Among Uveal Melanoma (UM) driver mutations, those involving GNAQ or GNA11 genes are the most frequent, while a minor fraction of tumors bears mutations in the PLCB4 or CYSLTR2 genes. Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas BRAFV600E-targeted therapy has obtained relevant results in cutaneous melanoma. However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets. In addition, BAP1 loss, which characterizes UM metastatic progression, affects chromatin structure via histone H2A deubiquitylation that may be counteracted by histone deacetylase inhibitors. Encouraging results of preclinical studies targeting signaling molecules such as MAPK and PKC were unfortunately not confirmed in early clinical studies. Indeed, a general survey of all clinical trials applying new targeted and immune therapy to UM displayed disappointing results. This paper summarizes the most recent studies of UM-targeted therapies, analyzing the possible origins of failures. We also focus on hyperexpressed molecules involved in UM aggressiveness as potential new targets for therapy.

Many renal cancer patients experience disease recurrence after immunotherapy or combined treatments due to persistence of cancer stem cells (CSCs). The identification of reliable inducers of CSC differentiation may facilitate the development of efficient strategies for eliminating CSCs. We investigated whether interleukin 15 (IL-15), a regulator of kidney homeostasis, induces the differentiation of CD105-positive (CD105⁺) CSCs from human renal cancers. CD105⁺ CSCs were cultured to preserve their stem cell properties and treated with recombinant human IL-15 (rhIL-15) to evaluate their ability to differentiate, to acquire sensitivity to chemotherapeutic drugs, and to form spheroids in vitro and tumors in vivo. Expression of stem cell and epithelial markers were studied by flow cytometry, immunocytochemistry, and immunoblotting. Identification of a CSC side population fraction and its sensitivity to chemotherapy drugs and expression of ATP-binding cassette (ABC) transporters and aldehyde dehydrogenase (ALDH) activities were determined by flow cytometry. Spheroid formation was determined in limiting dilution assay. Xenograft tumors were generated in severe combined immunodeficient mice (n = 12–18 mice per group). All statistical tests were two-sided. CD105⁺ CSCs treated with rhIL-15 at 10 pg/mL differentiated into cells expressing epithelial markers. rhIL-15 induced epithelial differentiation of all CD105⁺ CSCs subsets and blocked CSC self-renewal (sphere-forming ability) and their tumorigenic properties in severe combined immunodeficient mice. Vinblastine and paclitaxel induced statistically significant higher levels of apoptosis in rhIL-15-differentiated epithelial cells compared with CD105⁺ CSCs (mean percentage of apoptotic cells, vinblastine: 33% vs 16.5%, difference = 16.5%, 95% confidence interval = 12.25% to 20.74%, P = .0025; paclitaxel: 35% vs 11.6%, difference = 23.4%, 95% confidence interval = 22.5% to 24.24%, P = .0015). The higher sensitivity of rhIL-15-differentiated epithelial cells to chemotherapeutic drugs was associated with loss of detoxifying mechanisms such as ALDH and ABC transporter activities. IL-15 directs the epithelial differentiation of renal CSCs and meets the criteria for a treatment strategy: CSC pool depletion and generation of differentiated nontumorigenic cells that are sensitive to chemotherapeutic agents.