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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]

Background: Angiogenesis is a key and early step in tumorigenesis, and is known as a hallmark of solid tumors and a key promoter of tumor recurrence. Unlike normal tissue vessels, the architecture of the tumor vasculature is abnormal, being leaky, tortuous, fragile and blind-ended. Perivascular cells are either detached or absent, causing reduction of vascular integrity, an increase in vessel immaturity, incoherent perfusion, defective functionality and enhanced tumor dissemination and metastasis. The abnormal tumor vasculature along with the defective tumor vessel functionality finally causes bouts of hypoxia and acidity in the tumor microenvironment (TME), further reinvigorating tumor aggression. Interstitial hypertension or high interstitial fluid pressure (IFP) is an outcome of tumor hyper-permeability. High IFP can be a barrier for either effective delivery of anti-cancer drugs toward the TME or accumulation of drugs within the tumor area, thus promoting tumor resistance to therapy. Some tumors do, however, not undergo angiogenesis but instead undergo vessel co-option or vascular mimicry, thereby adding another layer of complexity to cancer development and therapy. Conclusions: Combination of anti-angiogenesis therapy with chemotherapy and particularly with immune checkpoint inhibitors (ICIs) is a promising strategy for a number of advanced cancers. Among the various approaches for targeting tumor angiogenesis, vascular normalization is considered as the most desired method, which allows effective penetration of chemotherapeutics into the tumor area, thus being an appropriate adjuvant to other cancer modalities. [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]

B7 homolog 3 (B7-H3, also called CD276) is a checkpoint of B7 family that is aberrantly and consistently expressed in several human cancers, and its overexpression correlates with weak prognosis. B7-H3 is expressed on a number of cells, and it acts as a driver of immune evasion. This is mediated through hampering T cell infiltration and promoting exhaustion of CD8+ T cells. Increased B7-H3 activity also promotes macrophage polarity toward pro-tumor type 2 (M2) phenotype. In addition, high B7-H3 activity induces aberrant angiogenesis to promote hypoxia, a result of which is resistance to common immune checkpoint inhibitor (ICI) therapy. This is mediated through the impact of hypoxia on dampening CD8+ T cell recruitment into tumor area. The immunosuppressive property of B7-H3 offers insights into targeting this checkpoint as a desired approach in cancer immunotherapy. B7-H3 can be a target in blocking monoclonal antibodies (mAbs), combination therapies, chimeric antigen receptor-modified T (CAR-T) cells and bispecific antibodies. • B7-H3 is overexpressed in tumor vs. normal tissue. • B7-H3 hampers CD8+ T cell infiltration and promotes their exhaustion. • B7-H3 poorly co-expresses with PD-L1. • B7-H3 can provide an alternative mechanism for bypassing ICI therapy. • Anti-B7-H3 biAbs act more selectively compared with monotherapy. [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]

• 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]

[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]

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]