One Step Ahead: Preventing Tumor Adaptation to Immune Therapy

Abstract

Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.

FIG 1.

Timeline of cancer immune therapy developments. Key developments in the discovery and clinical use or approval of immune therapy approaches to cancer treatment are depicted in a timeline extending from the late 1700s to the present day. Beginning with Edward Jenner’s development of the first formal vaccine against smallpox in 1796 and Wiiliam Coley’s use of heat-killed bacteria to treat patients with sarcoma, the field of cancer immune therapy has enjoyed a long history. The development and approval of precise and targeted immune therapy approaches are accelerating; in the past 15 years, numerous T-cell checkpoints have been described, their checkpoint inhibitors have been developed, and their clinical use has been refined. CAR-T cells have been clinically approved and are being refined. The first myeloid targeted therapy has been approved, and numerous others are in clinical or preclinical development. BCG, Bacillis Calmette-Guerin; CAR-T, chimeric antigen receptor T; CTLA-4, cytotoxic T lymphocyte associated protein 4; DC, dendritic cell; IL2, interleukin-2; mAb, monoclonal antibodies; RCC, renal cell carcinoma.

FIG 2.

Function and blockade of LAG-3. LAG-3 inhibits TCR signaling both through the function of the glutamic acid–/proline-rich EP motif, which occurs in both the absence and the presence of trans-ligand binding (top left), and through the function of the KIEELE and FSALE motifs in the presence of trans-ligand binding (top right). With LAG-3 bound to the TCR/CD3 complex (in cis), the EP motif alters local pH by sequestering zinc ions, leading to Lck dissociation from CD4/CD8 and blockade of TCR phosphorylation. The KIEELE domain is non–K48-polyubiquitinated in the presence of ligand binding, which frees the FSALE domain from the cell membrane (where it is otherwise buried) to inhibit TCR signaling. These mechanisms can be inhibited by blocking the homodimerization of LAG-3 (bottom left), which excludes it from the TCR/CD3 synapse and allows Lck function, or by blocking the binding of LAG-3 to MHCII (bottom right), which prevents KIEELE ubiquitination, leaving FSALE in the membrane and unable to inhibit TCR signaling. EP, glutamic acid/ proline rich motif; MHCII, major histocompatibility complex II; TCR, T cell receptor.

FIG 3.

Therapeutic approaches to prevent resistance to immune therapy. (A) The TME is characterized by immune-suppressive monocytes and granulocytes (sometimes called myeloid derived suppressor cells), which are recruited from circulation by chemokines and cytokines released from tumor cells, myeloid cells, fibroblasts, or T cells. These stimuli activate PI3Kγ, which promotes integrin activation and trafficking of myeloid cells into tumors. Tumor-associated monocytes and macrophages secrete cytokines and enzymes in a PI3Kgamma-dependent manner that suppresses T-cell activation and promotes tumor cell proliferation. (B) Chronic T-cell activation in the TME can lead to persistent IFNγ expression that promotes expression of immune checkpoints, including PD-1, LAG-3, and PD-L1, and that can induce IFNA expression and JAK1 activation in tumor cells. (C) Three therapeutic approaches, PI3Kγ inhibitors, LAG-3 antibody inhibitors, and JAK1 inhibitors, have been tested to prevent or combat resistance to anti–PD-1 and other immune therapies. (D) PI3Kγ and JAK1 inhibitors dampen recruitment of immune-suppressive myeloid cells into tumors. PI3Kγ inhibitors also block expression of immune-suppressive cytokines and promote T-cell activation by IL12 secretion. JAK inhibitors block IFNA-mediated signaling in tumors cells and enhance T-cell activation. LAG-3 antibodies prevent the immune-suppressive effect of LAG-3 expression. These three approaches similarly boost responses and prevent resistance to immune therapy. CTLA-4, cytotoxic T lymphocyte associated protein 4; DC, dendritic cell; EGF, epidermal growth factor; HGF, hepatocyte growth factor; IFNA, interferon alpha; IFNγ, interferon gamma; IL6, interleukin 6; IL10, interleukin 10; IL12, interleukin 12; MHC, major histocompatibility complex; mCSF, macrophage colony stimulating factor; NO, nitric oxide; PDGF, platelet derived growth factor; PI3Kγ, phosphoinositide 3-kinase gamma isoform; ROS, reactive oxygen species; TCR, T cell receptor; TGFb, transforming growth factor beta; TME, tumor microenvironment; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.