The field of immune checkpoint therapy has joined surgery, radiation, chemotherapy, and targeted therapy as a mainstay for cancer therapy. There are now an extensive number of therapeutic monoclonal anti bodies approved by the U.S. Food and Drug Administration (FDA), initially starting with melanoma in 2011–2014 and now available for a wide range of malignancies including kidney, lung, liver, head and neck, and gastric tumors (Table 1). Both CTLA-4 and PD-1 blockade have proved remarkably successful in treating a number of tumors, but only in a fraction of patients. Because each receptor ligand pair regulates distinct T-cell inhibitory pathways, combination therapy using anti-PD-1 and anti-CTLA-4 antibodies has been especially useful and has induced significant tumor regression in ~50% of melanoma patients. What is different in the use of checkpoint inhibitor antibodies is that the therapy is not targeted to the tumor per se, but rather is targeted to immunoregulatory molecules on host T cells. Moreover, therapy is not targeted to specific molecules on tumors, but rather is targeted to release exhausted tumor-infiltrating T cells (TILs) to be activated to kill tumor cells by removing immune regulatory inhibition.

Table1. Summary of the Tumor Types for Which Immune Checkpoint Blockade Therapies Are Approved by the U.S. Food and Drug Administration (FDA)

CTLA-4 induces tumor rejection by a number of mechanisms. First, anti-CTLA-4 antibody mediates direct blockade of CTLA-4 competition with CD28 for B7-1 and B7-2 co-stimulatory ligands, thus allowing CD28-mediated T-cell activation (Fig.1B). Tumor cells do not express B7 molecules; thus, CTLA-4 blockade likely occurs in tumor-draining lymph nodes where exhausted T cells interact with APCs presenting tumor neoantigens to T cells. A second mechanism of CTLA-4 blockade–induced tumor rejection is depletion or reduction in suppressive effects of Tregs. Suppressive effect of Tregs include secretion of immunosuppressive cytokines such as transforming growth factor (TGF)-β or interleukin- (IL) 10 or by direct inhibition of T-cell proliferation and/or cytolytic activity. A third potential mechanism of anti-CTLA-4 blockade is remodeling and broadening of the peripheral TCR repertoire for tumor antigens. Evidence suggests that the effects of anti-CTLA-4 antibody are restricted primarily to tumor neoantigen specific CD8 T cells within the tumor microenvironment and not to T cells in lymph nodes or spleen.

Fig1. Molecular mechanisms of CTLA-4 and PD-1 attenuation of T-cell activation and schematic of the molecular mechanisms of action of CTLA-4 and PD-1 blockade. A. Schematic of the molecular interactions and downstream signaling induced by ligation of CTLA-4 and PD-1 by their respective ligands. The possibility of additional downstream cell-intrinsic signaling mechanisms is highlighted for both CTLA-4 and PD-1. B. The stepwise progression of T-cell activation, attenuation by normal regulatory mechanisms, and release of such negative regulation by therapeutic intervention using anti-CTLA-4 or anti-PD-1 antibodies is outlined. (Reprinted from Cancer Discovery, 2018,8/9, 1069–1086, SC Wei et al: Fundamental Mechanisms of Immune Checkpoint Blockade Therapy, with permission from AACR.)

PD-1 blockade by PD-1 antibody also induces tumor regression by reversing T-cell exhaustion, leading to enhanced T-cell killing of tumor cells. Optimal PD-1 antibody-mediated checkpoint inhibition is seen when infiltrating CD8 T cells are present in the tumor micro environment and reversal of the exhausted T-cell state can occur in situ. PD-1 blockade can also act by reversal of metabolic reprogram ming of exhausted T cells, leading to enhanced cytolytic T-cell effector function. Antibodies to the primary PD-1 receptor, PD-L1, are also sufficient to induce reversal of T-cell exhaustion and induce tumor killing and are approved by the FDA for treatment of non-small-cell lung cancer (Table 1). PD-L1 is induced on tumor cells by TH 1 cytokines, which may explain anti-PD-L1 efficacy since TH 1 cytokines drive cytotoxic T-cell responses. Efficacy of anti-PD-L1 may also be due in part to mediation of antibody-dependent cellular cytotoxicity (ADCC) killing of tumor cells.

Tumor cells express neoantigens that are targets for T-cell recognition in the tumor microenvironment. Immune pressure within the tumor microenvironment can select for tumor cells that present few or mutated neoantigens and thus escape ongoing antitumor immunity. Moreover, a low number of tumor-infiltrating lymphocytes, tumor microenvironment production of immunosuppressive indoleamine 2,3-dioxygenase (IDO), and tumor infiltration with either myeloid derived suppressor cells or Tregs can also limit checkpoint blockade therapy.

Other strategies for improving the immunoregulation of antitumor responses include combinations of anti-PD-1, anti-CTLA-4, or anti PD-L1 antibodies with other checkpoint inhibitors. For example, engagement of the ICOS pathway enhances the efficacy of CTLA-4 blockade in animal models of cancer immunotherapy. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), TIGIT, or lymphocyte-activation gene 3 (LAG-3) inhibition has been suggested to enhance checkpoint inhibition and augment CD8 tumor cell killing. A new transcription factor, thymocyte-selection-associated high mobility box (TOX), has been defined as a key controller of CD8 T-cell exhaustion. Thus, TOX inhibition could synergize with checkpoint inhibition therapy to reverse the T-cell exhaustion state. The combination of checkpoint inhibition with other cancer treatments including chemotherapy, radiation, tumor signaling pathway inhibitors, and epigenetic modulators is being tested.

Modified mRNAs have revolutionized the field of infectious disease vaccine development, and this technology is now being applied to cancer vaccine development. Tumor neoantigens are being sequenced from individual patients, and mRNAs that encode them are being studied for their ability to boost antitumor CD8 T-cell responses. Messenger RNAs that encode individualized tumor antigens are being tested with checkpoint inhibitors such as pembrolizumab (anti-PD-1) or with traditional chemotherapy.

Anti-PD-L1 antibodies also mediate antitumor effects by ADCC, which utilizes natural killer (NK) effector cells. Indeed, a number of checkpoint inhibitor molecules have been found to be expressed on NK cells including CTLA-4, PD-1, LAG-3, TIGIT, and TIM-3. A new field of work is to target NK cells with existing checkpoint inhibitors and with antibodies against an NK-specific inhibitory molecule, NKG2A, that are designed release NK cells to kill tumor cells. One such anti-NKG2A antibody, monalizumab, has entered human clinical trials. NK cells also express natural cytotoxicity-activating receptors including NKp30, NKp44, and NKp46 receptors. Engagement of natural cytotoxicity-activating receptors in concert with the NK FcγRIII (CD16) and antibody against a tumor antigen also can enhance NK cell targeting of tumor antigens and is in preclinical development.

An important consequence of checkpoint blockade for cancer treatment is the frequent occurrence of immune-related adverse events (irAEs). Clinically, irAEs occur most often at skin, lungs, and the gastrointestinal (GI) tract—barrier sites to invading antigens. Colitis is among the most common irAE. Endocrinopathies with organ-specific autoantibodies such as antithyroid or antipituitary antibodies have also been reported. While the pathophysiology of irAEs is not fully known, it is likely that both checkpoint inhibitor–released autoimmunity with decreased inhibition of Treg cell function and bystander activation of immune cells with nonspecific inflammation contribute to checkpoint inhibitor side effects. The makeup of the gut microbiome can affect the efficacy of checkpoint inhibition therapy, and in addition, certain microbiome bacterial strains are associated with the occurrence of irAEs.

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المزيد

الآخبار الصحية

مفاجأة.. تحسين القدرة على التحمل لا يعتمد العضلات فقط

المرتفعات والأكسجين.. دراسة "مبشرة" لمرضى السكري

علماء يبتكرون "آلية" تتوقع موعد ظهور أعراض الزهايمر

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المزيد

الآخبار التكنلوجية

رصد "القرش النائم" في أحد أقسى الأماكن على وجه الأرض

أسماك أعماق البحر تكشف نظاما بصريا يتجاوز "المألوف"

زوكربيرغ أمام القضاء في قضية إدمان المراهقين

"علي بابا" تكشف عن نموذج جديد للذكاء الاصطناعي

المزيد

مواضيع ذات صلة

Chimeric Antigen Receptor T Cells

Mechanisms of Regulation of T-Cell Activation

Neutrophils & Eosinophils Employ Nets to Entrap Parasites

Immunotherapy

Immune Tolerance and Autoimmunity

Cellular interactions in regulation of normal immune responses

Markers of Granulocytic Maturation

The Complement System Also Protects Against Infection

Monocytopoiesis

Eosinophil Production

Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Cytokine Regulation of Myeloid Proliferation and Differentiation