In a recent study published in the journal Immunity, researchers reviewed the T cell response in cancer and autoimmunity to propose strategies for more effective immunotherapies.
Review: Learning from the nexus of autoimmunity and cancer. Image Credit: Meletios Verras / Shutterstock
Cancer and autoimmunity are positioned at opposite ends of the immune range; however, T cells play a central role in each disease condition. Moreover, while T cells get activated aberrantly in the former, damaging healthy tissues, their suppression in the latter fails to control malignant growth in cells. Thus, despite lying at opposite ends of the immune range, autoimmunity and cancer seem interconnected. This raises the possibility of T-cell targeting for therapeutic interventions.
In this regard, an in-depth understanding of the immune checkpoint blockade (ICB) phenomenon could be invaluable. In fact, it has helped achieve phenomenal results in multiple tumor states. Unfortunately, however, through tolerance disruption, ICB leads to immune-related adverse events (irAEs) in some patients, resembling what happens in autoimmunity.
An overexpression of immune checkpoint receptors on T cells due to repeated antigen stimulation could lead to T-cell dysfunction in cancer. Thus, understanding the molecular mechanisms governing this phenomenon could inform therapeutic intervention strategies that could help limit auto-reactive T cells driving autoimmune pathology.
Disruption of T cell tolerance to their regulation by immune checkpoint receptors
Central and peripheral tolerance processes regulate T cell specificity and activation. Thymus exhibits a remarkable example of central tolerance during the initial stages of T-cell development inside it. It ensures apoptosis of T cells whose receptors (TCRs) bind self-major histocompatibility complexes (MHCs) intensely. This process, working at 60 to 70% efficacy, eliminates all potentially auto-reactive T-cell clones.
For remaining auto-reactive T-cells, such as the cluster of differentiation (CD)4+ and CD8+ T cells against keratin (antigen), are taken care of by peripheral tolerance mechanisms, viz., active suppression, anergy, and clonal ignorance. Clonal ignorance, for instance, maintain self-reactive T cells in a naive/hyporesponsive state; however, that requires that the self-antigen is expressed only in those anatomical sites inaccessible to the immune system (e.g., testes, brain, and eyes).
Genome-wide association studies (GWASs) have shown a strong correlation of MHC-II alleles in elevating the risk of several autoimmune diseases, such as multiple sclerosis (MS), type 1 diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA).
Here, effector CD4+ T cells also help propagate and sustain autoimmunity. Like in infections-related cancers (e.g., cervical cancer), solid tumors, and hematologic cancers, GWAS has shown associations between MHC/non-MHC genes and immune processes. This data highlights the need to tailor future immunotherapies to unleash anti-tumor CD4+ T-cell responses to achieve persistent anti-tumor immunity.
Conventional T cells, upon activation, display CD152; however, regulatory T (Treg) cells have the highest levels of CD152 expression and its conditional deletion results in their hyperactivation leading to autoimmunity in humans. Similarly, the germline deletion of programmed cell death protein 1 (PD-1) could lead to autoimmunity in people with susceptible genetic makeup. For instance, a case report described how a child with inherited PD-1 deficiency had impaired immunity against tuberculosis that later resulted in fatal pulmonary autoimmunity.
Other immune checkpoints also come to the forefront upon repeated T-cell stimulation in autoimmunity and cancer, e.g., lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin-3 (TIM-3). These receptors are of great importance as their antagonism and agonism in cancer, and autoimmunity might lower the probability of therapy-related adverse events. Also, their high expression is characteristic of dysfunctional CD8+ T cells that show poor self-renewal ability and diminished effector functions. Dysfunction represents a peripheral tolerance mechanism and hinders developing anti-tumor immunity. Accordingly, researchers developed ICB therapies to interfere with dysfunctional phenotype. However, the engagement of dysfunction for autoimmunity could be beneficial.
Effect of steroid hormones on T cell regulation
Steroid hormones, including corticosteroids (e.g., glucocorticoids (GCs) and sex steroids (e.g., androgens), play significant roles in regulating the immune response in autoimmunity and cancer. They are all derivatives of the same steroid precursor (pregnenolone). Like GCs, androgen suppresses immunity rationalizing why most autoimmune diseases are more frequent in females than males, having higher circulating androgen levels. Similarly, males have a higher thymic autoimmune regulator (AIRE), which prevents autoimmunity by promoting self-tolerance during T-cell development. Ligand-bound androgen receptors (AR) also enhance AIRE transcription.
Accordingly, clinical studies have shown the efficacy of combinatorial ICB and anti-androgen therapy in prostate and bladder cancers. However, future studies should explore whether AR-driven effects on T cell differentiation also govern sex bias in autoimmunity. Furthermore, GCs have been the primary treatment to manage irAEs. For instance, high-dose GC is widely used in glioblastoma (GBM) therapy to dampen tumor-related vasogenic edema and treat elevated intracranial pressure. However, they have multiple side effects at high doses, including osteoporosis, and hypertension, to name a few. So the clinical application of GCs concerning dosage and duration should be carefully managed when given for the long term.
It is worth noting that immunotherapies-induced irAEs could occur during or post-therapy completion, though that is rare. Also, they most commonly affect some of the vital organs, including the liver and skin.
Role of biomarkers, pharmacogenomics, and GWASs to predict immune-related adverse events
Since the response to immunotherapies varies with every patient, insights into mechanisms that combat therapeutic resistance are crucial. In this context, biomarkers could help objectively quantify biological and pathological processes governing response to immunotherapies. identifying a lack of response early during treatment, biomarkers reduce the risk of drug failure. They also help identify patients at risk for developing autoimmune-resembling toxicities. For instance, auto-antibodies against insulin are detectable even in pre-symptomatic patients at risk of developing T1D.
Similarly, pharmacogenomics help identifies the genetic factors that determine individual response to a drug, including serious adverse drug reactions. Even GWASs have successfully identified subjects at high risk for developing cardiotoxicity following anthracyclines treatment.
Role of environmental and genetics in autoimmunity and cancer
Infections and dietary/lifestyle habits are environmental factors that possibly predispose or protect the host from developing autoimmune diseases and cancer, all of which come under the purview of a biological phenomenon called heterologous immunity. While this mechanism could help combat a new infection, in some cases, it could also trigger severe immunopathology by disrupting tolerance to self-antigens.
Similarly, obesity due to a lack of physical activity or unhealthy dietary habits could lead to several autoimmune diseases and cancer. Similarly, diets comprising more sugar and fat generate endocrinal and metabolic disturbances, which, in turn, disrupt the homeostasis of different immune populations. Poor dietary habits also disturb the commensal microbiome, some of which increase the recruitment of T helper cells 1-like CD4+ T cells to the tumor from the gut. The subsequent persistent inflammatory state generates mutagenic oxidative stress and impairs tissue immunosurveillance mechanisms that predispose a patient to both autoimmunities and cancers.
Although T-cell responses in cancer and autoimmunity appear opposing, there are some coalescing threads between the two. Researchers could exploit them to improve the efficacy of current immunotherapies and devise new ones; however, keeping in mind that with each relapse, the autoimmune response grows stronger, eventually transitioning to a chronic state that is highly therapy-resistant.
Further, the researchers proposed that future research accounts for disruptions in the natural rhythm of T-cell responses to diminish the inability to re-establish homeostasis and generate memory. Other holistic therapeutic approaches emphasizing better diet and lifestyle habits are also critical in the context of these diseases.
Although the immunotherapy revolution has just begun to unfold, examining the conjunction of discoveries in the domain of autoimmunity and cancer could be enlightening and help find the best ways to harness the immune system and improve the quality of life of patients suffering from these debilitating diseases.