Immune System Regulation
Cancer Cells, the Tumor Microenvironment, and the Immune System
Over the past 20 years, an exponential growth in data from basic scientific research in immunology and cancer biology has led to a greater understanding of the complex interactions between cancer and the immune system. Genetic and epigenetic changes within tumor cells lead to a distinct tumor antigen profile that can be recognized by the immune system. Genetic mutations often result in the development of tumor neo-antigens, while epigenetic modifications may lead to overexpression of genes (eg: HER2/Neu and EGFR), generating common tumor antigen targets for antibodies.1
Detection of neoplastic cells begins with the release of tumor-specific antigens through immunogenic or necrotic cell death. These neo-antigens are then presented to lymphocytes by macrophages or dendritic cells on major histocompatibility complex (MHC) molecules, leading to activation of T cells. Activated T cells infiltrate the tumor, recognize cells with the same tumor-specific antigen, and kill the cancer cells. Destruction of the cancer cell releases more antigenic material, increasing the immune response with each cycle.2 Each step of the cycle is controlled by numerous receptors and soluble factors, and the amplitude and quality of an immune response is regulated by the balance of co-stimulatory and inhibitory signals.3 A T cell response to antigen is only initiated if the T cell also receives co-stimulatory signaling, such as binding of CD80 to CD28 or dendritic cell-derived cytokines.4 T cell activation acts as an amplification signal and induces the release of cytokines such as interleukin (IL)-12 that stimulate the proliferation and activation of other effector T cells (eg, CD8+ cytotoxic T cells and CD4+ helper T cells) and the production of antigen-specific antibodies by B cells. T and B cells retain a life-long memory of the antigen, allowing faster tumor-specific immune response upon subsequent antigen detection.5,6 In order to prevent autoimmunity and minimize collateral tissue damage during immune responses, immune cells utilize immune checkpoints that inhibit T cell activity and promote immune regulatory feedback mechanisms.2
The activation of T cells may result in the elimination of cancer cells in early stages of tumor development, but studies have found this cytotoxic activity rarely results in durable protective immunity alone.2,7Accumulating evidence suggests that aberrant or “co-opted” immune responses are critical to cancer initiation and progression.4 Indeed, cancer cells exploit intrinsic regulatory and immunosuppressive mechanisms to promote tolerance and immune evasion. In particular, tumor antigens may not be detected or may be incorrectly identified as self; immune checkpoint receptors or ligands that suppress immune responses may be upregulated, or co-stimulatory molecules may be downregulated; and tumors or immune cells in the tumor microenvironment (eg, myeloid-derived suppressor cells and tumor-associated macrophages) may secrete cytokines or other substances that inhibit the activity of effector T cells.2,4,8 Cancer cells may also induce tolerance, in which the tumor turns off T cells that are specific for tumor antigens, thereby protecting themselves from elimination by the immune system.1
Analysis of tumor immune infiltrates has shown the presence of macrophages, dendritic cells, mast cells, natural killer cells, B cells and T cells.9In fact, a common feature of all cancers is chronic inflammation and the presence of diverse leukocyte subsets.10 Under continual selective pressure from the immune system, tumor cells become “immune-edited” and begin to evade immune system detection. Studies have shown that tumors with a greater number of T cell infiltrates are more amenable to treatment, driving the current trend to reprogram the tumor microenvironment to attract immune cells that can attack the tumor.4
Immunotherapies comprise a diverse group of strategies that are designed to initiate or augment a self-sustaining cycle of cancer immunity without inducing unchecked autoimmunity.2 Most of these strategies focus on T cells by regulating their activation and amplification, co-stimulatory signals, or cytokine secretion and lymphocyte attraction.11 Approaches that modulate immune checkpoints and boost specific antitumor immunity have provided proof-of-concept that immunotherapy can significantly improve outcomes for patients with advanced cancer, prompting the development of novel agents to extend this success.
Immune Checkpoint Inhibitors
Upregulation of inhibitory receptors is essential to balance the activity of co-stimulatory signals and limit T cell activation, thereby preventing autoimmunity, autoinflammation and tissue damage. Immune responses are tightly controlled and several regulatory mechanisms exist to maintain self-tolerance and prevent autoimmunity. For example, when presented with an antigen in the absence of a co-stimulatory signal, T cells remain unresponsive, or anergic, to prevent an attack against what they perceive as “self.” In addition, immune checkpoint proteins such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and lymphocyte activation gene-3 (LAG-3) block the effects of co-stimulatory molecules and induce upregulation of cytokines, such as IL-10, that reduce the immune response and promote the proliferation of immunosuppressive regulatory T cells.12,13
Unlike circulating tumor antigen-specific T cells which remain functionally competent, T cells found within tumors are “exhausted.” T cell exhaustion is likely caused by chronic exposure to large antigen loads, leading to antigen tolerance and severely impaired inflammatory and cytotoxic functions. Dysfunctional T cells present in malignant lesions are characterized by the sustained expression of a diverse set of inhibitory receptors known as immune checkpoints.14In the tumor microenvironment, immunosuppressive molecules such as CTLA-4, PD-1/PD-L1, and LAG-3 help the tumor to evade immune attack.15 CTLA-4 and PD-1 are receptors found largely on the surface of effector T cells. PD-L1 is a ligand for PD-1 that is broadly expressed and commonly upregulated on the tumor surface of many different cancers.16LAG-3 is an immune inhibitory receptor expressed on activated T cells, and it is co-expressed on tumor-infiltrating lymphocytes with PD-1.17The main function of these immune checkpoint proteins is inhibitory, dampening T-cell activation and effector function.3,18 CTLA-4 regulates T-cell activity at an early stage, whereas PD-1 regulates later effector T-cell activity within tissue and tumors.3 Immune checkpoints work as physiological brakes to prevent over activation of T-cells and thus prevent cell-mediated autoimmunity.19 PD-L1 can be expressed on tumor cells either endogenously or induced by association with T cells through adaptive immune resistance.3,20,21 Binding of PD-L1 to PD-1 leads to inhibition of intracellular signaling pathways controlling T cell activation.3 In addition, PD-1 is highly expressed on regulatory T cells infiltrating the tumor and their proliferation probably further suppresses effector immune responses. PD-1/PD-L1 interaction results in T cell suppression possibly via several mechanisms (i.e. anergy, exhaustion, and death).3 It has been postulated that blocking the PD-1:PD-L1 interaction with monoclonal antibodies directed to either PD-1 or PD-L1 leads to inhibition of the PD-1/PDL1 signaling pathway, re-activation of T lymphocytes, and thus generation of stronger anti-neoplastic responses.3,22
A class of novel immune oncology agents known as immune checkpoint inhibitors blocks these immunosuppressive molecules, thereby reactivating cytotoxic T cells and promoting tumor destruction. The first immune checkpoint inhibitor to display high antitumor activity was ipilimumab, an anti-CTLA-4 monoclonal antibody that blocks the interaction between the major negative regulator of T cells (CTLA-4) and its ligands (CD80 and CD86). Ipilimumab promotes the production of tumor-specific T cells by disinhibiting the expansion of T cell responses.2,15 Since then, the anti-PD-1 antibodies nivolumab, pembrolizumab and cemiplimab have demonstrated high activity in many types of cancer, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial cancer, head and neck cancer, hepatocellular carcinoma, and several hematologic malignancies. Additional agents that target immune checkpoints, including the PD-L1 inhibitors durvalumab, avelumab, and atezolizumab, and a second CTLA-4 inhibitor, tremelimumab, have also been developed.
CTLA-4 and PD-1 inhibit immune responses through complimentary and distinct mechanisms.23 CTLA-4 regulates T-cell proliferation early in an immune response to stop the activation of potentially autoreactive T cells. PD-1 inhibits T cell proliferation late in an immune response, often when the cell is “exhausted” after experiencing high levels of stimulation, such as during chronic infections or cancer. In theory, dual blockade of both CTLA-4 and PD-1 could induce proliferation of a higher number of T cells, restore responsiveness to exhausted T cells, and reduce regulatory T cell immunosuppression.16 Studies have shown that combination therapies may act synergistically to improve antitumor responses over monotherapy alone. In a trial comparing a combination of nivolumab with ipilimumab versus ipilimumab monotherapy in treatment naïve patients with advanced melanoma, significant improvements were seen in objective response rate and progression-free survival for combination therapy.
Despite the effectiveness of CTLA-4 and PD-L1/PD-1 targeted immunotherapies in a broad spectrum of tumor types, a large proportion of patients fail to respond to these agents. Some studies have found a correlation between increased expression of inhibitory receptors on T cells and progression of cancer. A high percentage of PD-1 expression on T cells correlates with poor restoration of T cell function upon PD-1 blockade with checkpoint inhibitors.24 Lymphocyte activation gene-3 (LAG-3) is a novel immunotherapeutic target that may work in combination with PD-1 to mediate T cell exhaustion. LAG-3 up-regulation is required to control overactivation of T cells and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG-3 expression, contributing to a state of T cell exhaustion. Regulatory T cells with LAG-3 receptors have increased suppressive activity, and CD8+ cytotoxic T cells with LAG-3 have reduced proliferation rates and effector cytokines production. Blocking LAG-3 restores cytotoxic T cell activity and the effect is synergistic with PD-1 blockade.17
- Pardoll D. Cancer and the immune system: basic concepts and targets for intervention. Semin Oncol. 2015 Aug;42(4):523-38.
- Chen D, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.
- Pardoll D. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer.2012;12:252-264.
- Palucka AK, Coussens LM. The Basis of Oncoimmunology. Cell. 2016 Mar 10;164(6):1233-47.
- Sukari A, Nagasaka M, Al-Hadidi A, Lum LG. Cancer Immunology and Immunotherapy. Anticancer Res. 2016 Nov;36(11):5593-5606.
- Zanetti M. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics. J Immunol. 2015 Mar 1;194(5):2049-56.
- Dunn G, Old L, Schreiber R. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137-148.
- Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450-61.
- Angell H, Galon J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. CurrOpinImmuno. 2013;25:261-267.
- Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science. 2013;339:286-291.
- Ferris R. Hiding in Plain Sight: How Cancer Evades the Immune System. Medscape Education Oncology. http://www.medscape.org/viewarticle/864396. August 24, 2016. Accessed June 13, 2017.
- Disis ML. Tumor Immunity: Exploring the Role of a Checkpoint. Medscape Education Oncology. May 13, 2014. http://www.medscape.org/viewarticle/824152. Accessed June 13, 2017.
- Kohrt H. Concepts in Immuno-oncology: Understanding the Key Players. Medscape Education Oncology. April 30, 2014. http://www.medscape.org/viewarticle/823638. Accessed Accessed June 13, 2017.
- Zippelius A, Batard P, Rubio-Godoy V, et al. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 2004;64:2865-73.
- Hodi F, O’Day S, McDermott D, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.
- Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106.
- Marmarelis MR, Aggarwal C. Combination immunotherapy in non-small cell lung cancer. Curr Oncol Rep. 2018;doi:10.1007/s11912-018-0697-7
- Garon E. Current Perspectives in Immunotherapy for Non-Small Cell Lung Cancer.Semin Oncol. 2015;42(Suppl 2):S11-S18.
- Abdel-Rahman O, Elhalawani Risk of fatal pulmonary events in patients with advanced non-small-cell lung cancer treated with EGF receptor tyrosine kinase inhibitors: a comparative meta-analysis.Future Oncol. 2015;11:1109-1122.
- Topalian S, Hodi F, Brahmer J, et al. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med.2012;366:2443-2454.
- Taube J, Anders R, Young G, et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127-137.
- Intlekofer A, Thompson At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy.J Leukoc Biol. 2013;94:25-39.
- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017.
- Thommen DS, Schreiner J, Muller P, et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res. 2015;3(12):1344-55.