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Background: Immunotherapy using immune checkpoint inhibitors (ICIs) is the current focus in cancer immunotherapy. However, issues are raised in the area, as the recent studies showed that such therapeutic modality suffers from low durability and low or no efficacy for patients with some tumor types including cases with non‐inflamed or cold cancers. Therefore, efforts have been made to solve the issue using immune combination therapy, such as the use of immunocytokines. The combination of ICI with interleukins (ILs) and IL‐targeting agents is now under consideration in the area of therapy, and the primary results are promising. Purpose: The focus of this review is to discuss the possibility of using ILs and IL‐targeting drugs in combination with ICI in cancer immunotherapy and describing recent advances in the field using PEGylated ILs and fusion proteins. The key focus in this area is to reduce adverse events and to increase the efficacy and durability of such combination therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor-modified T (CAR-T) are genetically engineered cells to express tumor-specific antigens revolutionizing the treatment of hematologic malignancies. The hostile tumor microenvironment (TME) remains a challenge for CAR-T cell therapy in solid tumors. As a solution, combinational therapy with immune checkpoint inhibitors (ICIs) is shown to improve the safety and efficacy of CAR-T cell therapy. To avoid side effects related to the application of ICIs in combinational therapy, engineering CARs to express tumor-specific antigens may help improvement of clinical outcomes. Those CARs expressing single chain variable fragments (scFvs) or nanobodies against immune checkpoint stimulatory or inhibitory molecules, such as the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis are being extensively studied in various clinical trials. In this review, we discuss the significance of anti-PD-(L)1 scFv-expressing CAR-T cells in the treatment of human cancers, describing current challenges and potential strategies to overcome such predicaments in the area of cancer immunotherapy. [Display omitted] • CAR-T can be a strategy for revolutionizing ICI efficacy. • Anti-PD-(L)1-expressing CAR-T shows equal or better efficacy vs. separate combinational therapy. • Anti-PD-(L)1-expressing CAR-T minimizes toxicities related to systemic ICI application. [ABSTRACT FROM AUTHOR]

• Aberrant B7x expression occurs in human cancers. • B7x preferentially expresses in APCs and tumor cells. • B7x promotes immune escape and associates with poor tumor cell differentiation. • B7x expression inversely correlates with PD-L1 expression profile. • B7x receptor is co-expressed with PD-1 on CD8+ T cells. • Anti-B7x can be used synergistically with anti-PD-(L)1 or anti-CTLA-4. • Bispecific inhibitors against B7x and other regulatory molecules are underway. B7x (also called B7-H4) is a co-inhibitory molecule of B7 family that is highly expressed in non-inflamed or cold cancers, and its aberrant expression is contributed to cancer progression and poor outcomes. B7x preferentially expresses on antigen-presenting cells (APCs) and in tumor cells, and it acts as an alternative anti-inflammatory immune checkpoint for hampering peripheral immune responses. Augmented infiltration of immunosuppressive cells, reduced proliferation and effector function of CD4+ and CD8+ T cells, and increased generation of regulatory T cells (Tregs) are outcomes of increased B7x activity in cancer. Evaluation of B7x in sera can be exploited as an effective biomarker of response in cancer patients. B7x overexpression generally occurs in programmed death-ligand 1 (PD-L1)- cancers and is involved in tumor resistance to anti-programmed death-1 (PD-1), anti-PD-L1 or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) therapy. Co-expression of B7x receptor with PD-1 on CD8+ T cells has made the anti-B7x a fruitful approach for reinvigoration of the functionality of exhausted T cells and is served as a complementary regimen in patients who are irresponsive to the common immune checkpoint inhibitor (ICI) therapy. An advance in the field is the development of bispecific antibodies against B7x with other regulatory molecules within tumor microenvironment (TME). [ABSTRACT FROM AUTHOR]

Resistance to immune checkpoint inhibitors (ICIs) is a major issue of the current era in cancer immunotherapy. Immune evasion is a multi-factorial event, which occurs generally at a base of cold immunity. Despite advances in the field, there are still unsolved challenges about how to combat checkpoint hijacked by tumor cells and what are complementary treatment strategies to render durable anti-tumor outcomes. A point is that anti-programed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) is not the solo path of immune escape, and responses in many types of solid tumors to the PD-1/PD-L1 inhibitors are not satisfactory. Thus, seeking mechanisms inter-connecting tumor with its immune ecosystem nearby unravel more about resistance mechanisms so as to develop methods for sustained reinvigoration of immune activity against cancer. In this review, we aimed to discuss about common and specific paths taken by tumor cells to evade immune surveillance, describing novel detection strategies, as well as suggesting some approaches to recover tumor sensitivity to the anti-PD-(L)1 therapy based on the current knowledge. • Resistance to anti-PD-(L)1 is multi-factorial. • Defective infiltration and effector CD8+ T cells is a critical driver of ICI resistance. • PD-L1 high MHC-I low tumor cell signature is a reliable biomarker of ICI resistance. [ABSTRACT FROM AUTHOR]

Resistance to immune checkpoint inhibitors (ICIs) is a common predicament in cancer immunotherapy, which requires urgent interventions. V-domain immunoglobulin suppressor of T cell activation (VISTA) or programmed death-1 homolog (PD-1H) is a molecule belong to the CD28/B7 family that acts as an immune checkpoint and a negative immune regulator. VISTA shows high expression within tumor microenvironment (TME) and shapes the immune landscape of this milieu into an immunosuppressive entity through blunting the activity of anti-tumor cells and strengthening the power of pro-tumor cells. The increased expression profile is occurring essentially after inhibition of other checkpoints, which indicates that VISTA can constitute a novel and complementary target in cancer immunotherapy. Combination of anti-VISTA with appropriate ICIs potentiates tumor immunogenicity through increasing the effector activity of T cells, and results in more pronounced responses. VISTA also serves as a prognostic biomarker in differentiating early- from late-stage cancer. In this review, we aimed to discuss about VISTA and its regulation within TME and focusing on its prognostic and therapeutic values in cancer immunotherapy. [Display omitted] • VISTA is overexpressed particularly on myeloid progeny. • VISTA is upregulated secondary to the anti-PD-1/PD-L1 or anti-CTLA-4. • VISTA activity on T cells is independent on PD-1/PD-L1 or CTLA-4. • VISTA is an independent prognostic marker. • Dual VISTA/PD-L1 blockade represents promising clinical efficacy. [ABSTRACT FROM AUTHOR]

Combination therapy of solid tumors with immune checkpoint inhibitors (ICIs) is a promising and rapidly evolving area of clinical research. Combo nivolumab-ipilimumab therapy has demonstrated potent efficacy in recent years, and PD-L1 expression profile has shown to play a key role in determining the most optimal immunotherapeutic regimen in advanced cancer patients. Here, the focus is over the impact of PD-L1 on combo nivolumab-ipilimumab in advanced solid cancer patients. Interpretations of this review indicate that patient responses to combo nivolumab-ipilimumab can be affected from different levels of PD-L1 expression states. A point required attention is the variations in responses among diverse cancer types or between different doses of the immunotherapy drugs. In general, higher rates of responses are seen with higher PD-L1 expression levels in many cancer types. This, however, is not coincided with survival of patients. Taken all into consideration, it could be asserted that considering PD-L1 as a solo biomarker may not be reliable for predicting clinical efficacy of combo nivolumab-ipilimumab. Thus, a search for other biomarkers or combination of PD-L1 with other factors may be considered for predicting patient responses. • PD-L1 is tightly regulated in TME. • PD-L1/PD-1 activity hampers T cell effector function. • PD-L1 levels associate with objective responses to nivolumab-ipilimumab. • Patient survival is seemingly not affected from PD-L1 level. • Combo PD-L1 with other factors is suggested for response prediction in advanced cancers. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized treatment of cancer during the last decades. Oncolytic virotherapy has also emerged as a strategy to fight against cancer cells both via lysis of malignant cells and activating immune responses. Accepted as a logical strategy, combination of monoclonal antibodies particularly against the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) is introduced to improve clinical responses to immune checkpoint inhibitors (ICIs). Accordingly, Talimogene laherparepvec (T-VEC) has received approval for clinical use, while a number of oncolytic Adenoviruses (Ads) are being investigated in clinical trials of malignancies. Combination of oncolytic Ads with PD-1/PD-L1 inhibitors have shown potentials in promoting responses to ICIs, changing the tumor microenvironment, inducing long-term protection against tumor, and promoting survival among mice models of malignancies. Regarding the increasing importance of oncolytic Ads in combination therapy of cancers, in this review we decide to outline recent studies in this field. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment in the last decade. Among various checkpoints identified so far, interaction between programmed death-1 (PD-1) with programmed death ligand 1 (PD-L1) and their targeting using human monoclonal antibodies has attracted the most attention and is considered as the most prominent treatment with the best clinical outcomes. Accumulating evidence is the witness for the impact of gut microbiota on clinical responses and ICI efficacy. Specific bacterial species are identified in fecal specimens of cancer patients responding to the anti-PD-(L)1 immunotherapy, while non-responders demonstrate high abundance of other bacterial sources. Thus, the composition of gut microbiota may suggest potential biomarker in identification of patients with the best responses to immunotherapy. Notably, fecal microbial transplantation (FMT) from responders to non-responders has shown hopeful results in improving clinical outcomes and overcoming resistance to ICIs. Additionally, some bacterial components, such as the use of antibiotics and probiotic supplements have been shown to affect the efficacy of ICIs treatment. However, employment of these findings requires further investigations and precise understanding of the impact of gut microbiota on the host's immune responses. In the current review, we aim to discuss the roles of PD-1/PD-L1 checkpoint pathway, their therapeutic significance, and the impact of gut microbiota/products on the PD-1/PD-L1 immunotherapy outcomes. The impact of gut microbiota on ICI responses. Specific bacterial species are identified in fecal specimens of cancer patients responding to the anti-PD-(L)1 immunotherapy, while non-responders demonstrate high abundance of other bacterial sources. Thus, the composition of gut microbiota may suggest potential biomarker in identification of patients with the best responses to immunotherapy. [Display omitted] • PD-1/PD-L1 axis plays crucial roles in regulation of immune responses. • Tumor cells exploit the PD-1/PD-L1 axis to escape from immunosurveillance. • Gut microbiota affects the efficacy and responses to ICIs in cancer patients. • FMT can improve anti-cancer responses in ICI-treated patients. [ABSTRACT FROM AUTHOR]