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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]

• TGF-β promotes anti-tumor immune cell exclusion and dysfunction. • TGF-β and PD-L1 show independent but complementary immunosuppressive potentials. • Anti-PD-L1/TGF-βRII trap agents enable PD-L1 saturation and TGF-β sequestration. • M7824 is more effective in PD-L1high or immune-excluded tumors. Immune checkpoint inhibitor (ICI) therapy suffers from tumor resistance and relapse in majority of patients due to the suppressive tumor immune microenvironment (TIME). Advances in the field have brought about development of fusion proteins able to target two signaling simultaneously and to exert maximal anti-cancer immunity. Bispecific inhibitors of transforming growth factor (TGF)-β signaling and programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are developed to reduce the rate of relapse and to achieve durable anti-cancer therapy. TGF-β is well-known for its immunosuppressive activity, and it takes critical roles in promotion of all tumor hallmarks. Bispecific anti-PD-(L)1/TGF-β inhibitors reinvigorate effector activity of CD8+ T and natural killer (NK) cells, hamper regulatory T cell (Treg) expansion, and increase the density of anti-tumor type 1 macrophages (M1). Responses to the bispecific approach are higher compared with solo anti-PD-(L)1 or TGF-β targeted therapy, and are seemingly more pronounced in human papillomavirus (HPV)+ patients. High expression of PD-L1 or immune-excluded phenotype in a tumor can also be markers of better response to the bispecific strategy. Besides, anti-PD-(L)1/TGF-β inhibitor therapy can be used safely with other therapeutic modalities including vaccination, radiation and chemotherapy. [ABSTRACT FROM AUTHOR]

Extending the durability of response is the current focus in cancer immunotherapy with immune checkpoint inhibitors (ICIs). However, factors like non-immunogenic tumor microenvironment (TME) along with aberrant angiogenesis and dysregulated metabolic systems are negative contributors. Hypoxia is a key TME condition and a critical promoter of tumor hallmarks. It acts on immune and non-immune cells within TME in order for promoting immune evasion and therapy resistance. Extreme hypoxia is a major promoter of resistance to the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. Hypoxia inducible factor-1 (HIF-1) acts as a key mediator of hypoxia and a critical promoter of resistance to the anti-PD-(L)1. Targeting hypoxia or HIF-1 can thus be an effective strategy for reinvigoration of cellular immunity against cancer. Among various strategies presented so far, the key focus is over vascular normalization, which is an approach highly effective for reducing the rate of hypoxia, increasing drug delivery into the tumor area, and boosting the efficacy of anti-PD-(L)1. • Hypoxic TME is a key promoter of ICI resistance/refractory. • High PD-L1 level is a marker of poor prognosis but higher response to ICIs. • Aberrant angiogenesis/hypoxia/dysregulated metabolism promote T cell exclusion/exhaustion. • Vascular normalization dampens tumor hypoxia and promotes ICI sensitization. • Low-dose anti-angiogenic therapy increases ICI sensitivity. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) resistance demands for acquisition of novel strategies in order to broaden the therapeutic repertoire of advanced cancers. Bispecific antibodies can be utilized as an emerging therapeutic paradigm and a step forward in cancer immunotherapy. Synchronous inhibition of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1) or cytotoxic T lymphocyte associated antigen-4 (CTLA-4), or with other agents can expand antibody selectivity and improve therapeutic window through tightening cell-to-cell bridge (a process called immunological synapse) within tumor immune microenvironment (TIME). There is evidence of higher potency of this co-targeting approach over combined single-agent monoclonal antibodies in reinvigorating anti-tumor immune responses, retarding tumor growth, and improving patient survival. In fact, immunological synapses formed by interactions of such bispecific agents with TIME cells directly mediate cytotoxicity against tumor cells, and durable anti-tumor immune responses are predictable after application of such agents. Besides, lower adverse events are reported for bispecific antibodies compared with individual checkpoint inhibitors. These are all indicative of the importance of exploiting novel bispecific approach as a replacement for conventional combo checkpoint inhibitor therapy particularly for tumors with immunosuppressive or cold immunity. Study in this area is still continued, and in the future more will be known about the importance of this bispecific approach in cancer immunotherapy. • Bispecific inhibitors are more effective compared with combination of single-agent mAbs. • Lower adverse events are reported for bispecific (vs. monospecific) antibodies. • Bispecific inhibitors reactivate anti-cancer T cells more selectively. [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]

[Display omitted] • IDO1 induces immune tolerance within TME. • Serum profiling of IDO1 metabolites is of prognostic value. • IDO1 upregulation occurs after ICI therapy. • IDO1 inhibitors can be used safely with ICI therapy. • Epacadostat plus ICI renders promising clinical responses. • Clinical efficacy of anti-PD-L1/IDO inhibitor vaccination is promising. Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper. [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]

Tumor microenvironment (TME) takes critical roles in tumor resistance to immune checkpoint inhibitors (ICIs) including anti-programmed death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1). Cancer stem cells (CSCs) are one of the key components of TME that play important roles in immunoregulation and therapy resistance. CSCs suppress CD8+ T cell infiltration, and promote recruitment of type 2 macrophages (M2) and the activity of type 2 neutrophils (N2). There is a positive association between CSC expansion with high PD-L1 expression in TME, and the expression of PD-L1 is higher in CSCs than cancer cells. PD-L1 expression in metastatic cancer cells induces a dedifferentiation program through stimulating an epithelial-mesenchymal transition (EMT) profile, thereby replenishing CSC proportion inside tumor. Conversion from EMT to mesenchymal-epithelial transition (MET) downregulates PD-L1 expression on CSCs and non-CSCs and increases ICI efficacy. There is an evidence of CSC replenishment secondary to the anti-PD-1 therapy. Targeting CSCs is, in fact, a key step in effective tumor breakdown and reducing tumor recurrence after immunotherapy. A number of signaling are involved in CSC enrichment within tumor area, among them a key focus is over transforming growth factor-β (TGF-β). TGF-β induces a dedifferentiation program, and its activity as a bridge between EMT with increased PD-L1 level rationalizes application of dual TGF-β/anti-PD-L1 inhibitors as an effective strategy for reinvigorating immunoactivities in patients under ICI therapy. In this review, we aimed to discuss about connections between CSCs with immune ecosystem of tumor and the impact of such interactions on cancer responses to ICI therapy. • The impact of CSCs on tumor immune ecosystem is necessary for hampering ICI efficacy. • EMT is strongly associated with increased expression of immune checkpoints. • MET conversion can be an approach for tumor sensitization to the ICI therapy. • TGF-β is a key CSC inducer that links EMT with increased PD-L1 level in tumor area. • CSCs can be targeted to boost ICI efficacy. • Tumor heterogeneity is linked positively with CSC characteristics and affects ICI responses. [ABSTRACT FROM AUTHOR]