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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]

Radiotherapy is a common modality for more than half of cancer patients. Classically, radiation is known as a strategy to kill cancer cells via direct interaction with DNA or generation of free radicals. Nowadays, we know that modulation of immune system has a key role in the outcome of radiotherapy. Selecting an appropriate dose per fraction is important for stimulation of anti-tumor immunity. Unfortunately, cancer cells and other cells within tumor microenvironment (TME) promote some mechanisms implicated in the attenuation of anti-tumor immunity via exhaustion of CD8 + T lymphocytes and natural killer (NK) cells. Immunotherapy with immune checkpoint inhibitors (ICIs) has shown to be an interesting adjuvant for induction of more effective anti-tumor immunity. Clinical trial studies are ongoing for uncovering more knowledge about the efficacy of ICI combination with radiotherapy. Some newer pre-clinical studies show more effective therapeutic window for targeting PD-1 and some other targets in combination with hypofractionated radiotherapy. In this review, we explain cellular and molecular consequences in the TME following radiotherapy and promising immune targets to enhance anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Incapacitated immune system is a characteristic hallmark of solid tumors. Immune system within a tumor undergoes an imbalance in cellular dispersion and functionality. Effector cells are precluded from the invasive margin of tumor; instead, immune suppressor cells are present at high fractions. Conditions in the tumor microenvironment (TME) like altered metabolism, chronic hypoxia and chronic inflammation are the known predisposing factors, implicated in the immune malfunctioning. Deficiency of innate immune sensing mediated by checkpoint receptors including programmed death-1 receptor (PD-1), CTL-associated antigen-4 (CTLA-4) hijacked by tumor cells takes a major part of the blame, requiring a need for appropriate strategies in order to bring back the balance in the immune system. Immune checkpoint inhibitor (ICI) therapy has been in the eye of the current research rendering promising results. The story is not, however, that easy in which it is not so effective for Cold tumors, it may cause severe adverse effects, and that patients may acquire resistance to such therapy; this requires for updating the current knowledge about the immune ecosystem, using tumor type dependent dose calculation and exploiting proper adjuvants in order for evolving desired responses. Unlabelled Image [ABSTRACT FROM AUTHOR]