Cancer Immunoediting in the Era of Immuno-oncology

Abstract

Basic science breakthroughs in T-cell biology and immune-tumor cell interactions ushered in a new era of cancer immunotherapy. Twenty years ago, cancer immunoediting was proposed as a framework to understand the dynamic process by which the immune system can both control and shape cancer and in its most complex form occurs through three phases termed elimination, equilibrium, and escape. During cancer progression through these phases, tumors undergo immunoediting, rendering them less immunogenic and more capable of establishing an immunosuppressive microenvironment. Therefore, cancer immunoediting integrates the complex immune-tumor cell interactions occurring in the tumor microenvironment and sculpts immunogenicity beyond shaping antigenicity. However, with the success of cancer immunotherapy resulting in durable clinical responses in the last decade and subsequent emergence of immuno-oncology as a clinical subspecialty, the phrase "cancer immunoediting" has recently, at times, been inappropriately restricted to describing neoantigen loss by immunoselection. This focus has obscured other mechanisms by which cancer immunoediting modifies tumor immunogenicity. Although establishment of the concept of cancer immunoediting and definitive experimental evidence supporting its existence was initially obtained from preclinical models in the absence of immunotherapy, cancer immunoediting is a continual process that also occurs during immunotherapy in human patients with cancer. Herein, we discuss the known mechanisms of cancer immunoediting obtained from preclinical and clinical data with an emphasis on how a greater understanding of cancer immunoediting may provide insights into immunotherapy resistance and how this resistance can be overcome.

Figure 1:. The cancer immunoediting process.

The cancer immunoediting hypothesis provides a framework to decipher the dynamic and complex interactions between immune cells and cancer cells within the tumor microenvironment. These interactions may be anti-tumor or pro-tumor; thereby highlighting the dual role of immune cells in both preventing tumors from growing and/or enhancing tumor growth. Cancer immunoediting consists of three phases: Elimination, Equilibrium, and Escape. Elimination is the first phase of cancer immunoediting, whereby the innate and adaptive immune system act in concert to destroy the nascent tumor, thus leading to tumor destruction and tissue homeostasis or normalization. When the immune system fails to eradicate the tumor cells, the cancer may enter the equilibrium phase where its outgrowth is immunologically restrained, but the cancer is not eliminated. Further immunological sculpting of the tumor and establishment of a suppressive tumor microenvironment may lead to the escape phase of cancer immunoediting, where the cancer becomes clinically apparent disease and spreads to other organs.

Figure 2:. The development of immuno-oncology.

Fundamental insights into T cell activation and inhibition in the late 20^th century provided the rationale to targeting immune inhibitory receptors such as CTLA-4 and PD-1 or PD-L1 to treat cancer in pre-clinical cancer models. At the beginning of the 21^st century, successful targeting of “immune checkpoints” ushered in the first clinical trials in human cancer patients. Cancer immunotherapy provided greater response rates with longer duration than traditional chemotherapy for some cancers. Subsequently, the subspecialty immuno-oncology was borne dedicated to the study and development of cancer immunotherapies, the immunologic monitoring of responses and adverse events of patients treated with cancer immunotherapies and tailored clinical treatment paradigms. Insights gained from immuno-oncology are often then brought back to the research laboratory in ‘reverse translation’ to overcome challenges such as resistance to immunotherapy.

Figure 3:. Cancer immunoediting occurs naturally and during cancer immunotherapy.

A) Cancer immunoediting was initially described during natural immune-tumor cell interactions in the absence of immunotherapy. During natural anti-tumor immunity, the immune system may detect and destroy a nascent tumor during the elimination phase, resulting in immunosurveillance and prevention of clinically detectable cancer. Tumors may enter a dynamic equilibrium between pro-tumor and anti-tumor effects, resulting in tumor dormancy. However, subsequent immunoediting of tumor immunogenicity may result in the development of an immunosuppressive tumor microenvironment and dysfunctional anti-tumor immune response that outweighs anti-tumor effects, resulting tumor escape and subsequent cancer. B) Cancer immunoediting is a continually process that also occurs during cancer immunotherapy of established advanced cancers in human patients. If successful, cancer immunotherapy can correct or normalize a dysfunctional immune response in the tumor microenvironment and drive the elimination of the tumor with resultant durable benefit. If complete elimination of the tumor is not achieved with immunotherapy, there could be an establishment of the equilibrium phase where the patient’s cancer partially responds to therapy and still has durable benefit. However, many cancers fail to respond to specific immunotherapies and continue to escape immune control. These non-responders either never respond to immunotherapy (primary resistance) or initially respond to treatment, but then undergo further immunoediting and subsequent escape (secondary or acquired resistance).

Figure 4:. Adaptive immune resistance.

Upon T cell detection of cancer and activation, antigen-specific T cells produce IFN-γ to eliminate cancer. However, some cancers and myeloid cells such as macrophages or dendritic cells (DCs) upregulate PD-L1 (also known as B7-H1) in response to immune attack and IFN-γ signaling. Subsequent upregulation of PD-L1 binds to activated T cells expressing PD-1 and inhibits T cells in a process termed adaptive immune resistance. Targeting this local, dysfunctional immune response within the tumor microenvironment with anti-PD-1 or anti-PD-L1 immunotherapy, reduces the T cell inhibition, allowing the T cells to become re-activated and eliminate cancer cells through cytokines (IFN-γ, TNFα) and cytolytic programs with perforin (PFN) and granzyme B (GzmB). Targeting adaptive immune resistance with anti-PD-1/PD-L1 therapy is an example of normalization cancer immunotherapy.

Figure 5:. Cancer immunoediting shapes tumor immunogenicity with impacts for patient-centered cancer immunotherapy.

The dynamic immune-tumor cell interactions generate significant tumor microenvironment heterogeneity. Two key features for anti-tumor immunity and elimination of cancer include immune detection of cancers and immune killing of cancer. The cancer immunoediting process sculpts tumor immunogenicity through a variety of mechanisms that affect either immune detection or killing of cancers. Escape from immune detection may include antigen immunoselection, defects in antigen presentation, loss of interferon signaling pathways and T cell exclusion. Escape from immune killing may include expression of immune inhibitory molecules (“immune checkpoints”) that inhibit T cell function, secreted immunosuppressive factors, recruitment of immunosuppressive immune cells, and exclusion of T cells. T cell exclusion by either secreted factors or stromal barriers inhibits both immune detection and killing of caners. Together, immunoediting of the tumor microenvironment creates unique tumor-immune microenvironments (TIME) that stratifies responses to immunotherapies. For example, classifying tumors by the presence of tumor infiltrating T cells (TILs) and expression of immunotherapy target PD-L1 creates four distinct TIME subclassifications that affects response to anti-PD immunotherapy (63, 67): type I (neither PD-L1 nor TILs present); type II (both PD-L1 and TILs present); type III (no PD-L1, but TILs present); and type IV (PD-L1 present, but no TILs). More broadly, TIME can be considered as either ‘hot’ tumors with significant immune infiltration or “cold” tumors with little infiltration or anti-tumor immunity. Unique immunotherapy strategies are needed for each unique TIME for a patient-centered caner immunotherapy.