We hypothesized that presence of diabetes before ICI treatment would be associated with fewer irAEs in patients receiving treatment for advanced lung cancer. However, diabetes was not associated with the rate of irAEs, although it was associated with shorter PFS in this patient group. The structural and conformational dynamics of the immune-related cancer agents nivolumab and pembrolizumab are referred to as anti–PD-1 antibody (1). Tumor cells express programmed death-ligand 1 (PD-L1) on their surface, to avoid attack from the immune system. However, PD-L1 binds to PD-1, which is expressed on the surface of T cells, thereby suppressing the immune system. Anti–PD-1 antibody binds to PD-1, thus inhibiting interaction of cancer cells and immune cells (19). However, this immunotherapeutic approach is often associated with immune-mediated toxic events, known as irAEs. Interestingly, irAEs were found to be associated with improved OS and cancer-specific PFS in several advanced cancers (11)(12).
Diabetes And Immune Reactivity
Recognize immune systems by several T cell clones of its cognate antigen results in the initiation of an immune response (20). A recent study reported that diabetes is a chronic, low-grade inflammatory disease in which expression or activation of immune-related molecules is altered (21). T cells differentiate various types of immune cells by specific stimulation and the source of energetic nutrient transport. Under conditions of normoglycemia, naive T cells use lipids as their predominant energy substrate to differentiate regulatory T cells. However, under conditions of hyperglycaemia, glucose is mainly used as the energy substrate to differentiate to Th17 (22)༎Furthermore, PD-1 expression on tumor cell surfaces is diminished in diabetes, which blunts the response to activated T cells (23)༎Although hyperglycaemia, including diabetes, is known to alter immune T cell activity, the response to ICIs in the context of advanced cancer treatment is not well understood. Our findings showed no association between diabetes before ICI and irAE incidence, which was associated with subsequent OS and PFS. The results were similar in the PFS-matched cohort and overall, unmatched cohort.
Diabetes And Cancer-specific Outcomes
Ten percent of the world population will develop diabetes during their life (24), 55% of whom will receive a cancer diagnosis. Reverse causality may play a role in diabetes and cancer, and the link between the two diseases facilitates further development and vice versa. PFS was poor in the present patients with diabetes. Diabetes before ICI treatment was associated with worse PFS in lung cancer patients, and pre-treatment diabetes was associated with poor outcomes after chemotherapy for other cancers (25)(26).
Diabetes and cancer share several intrinsic risk factors (obesity, poor diet, and aging) (25), and our results indicate that diabetes was associated with worse OS and PFS, regardless of irAE development. Although the underlying biological mechanisms are unclear, several hypotheses have been suggested. First, hyperinsulinemia and hyperglycaemia associated with diabetes may increase tumor cell proliferation and metastasis (25). Adipose tissue inflammation may play a role, and insulin resistance might further enhance production of inflammatory cytokines, which could alter the immune system (25). Secondly, patients with diabetes are more likely to develop adverse effects during chemotherapy, which decreases the effectiveness of such treatments (25)(26). Although ICIs clearly improve outcomes in patients with advanced lung cancer, they are costly and associated with adverse events (irAEs). In our current health care environment, policy makers, providers, and patients need more evidence, to determine the value of therapeutic alternatives to ICI treatment. We must examine covariates that might affect ICI effectiveness. Inappropriate ICI treatment results in detrimental risks, both in social health costs and patient selection bias. Our results shed light on the positive effects of ICIs on OS and PFS in patients without diabetes before ICI treatment.