Interaction of Breast Cancer and Insulin Resistance on PD1 and TIM3 Expression in Peripheral Blood CD8 T Cells

Abstract

Epidemiological evidence points to a link between insulin resistance (IR) and breast cancer (BrCA). Insulin plays a role in CD8+ T cells (CD8T) differentiation and function and affects adipocytokines levels. CD8T activity in BrCA is associated with favorable outcome; while PD1 and TIM3 are markers of CD8T exhaustion and play critical roles in the negative regulation of T cell responses. Patients with (BrCA) have high expression levels of PD1 on circulating. Therefore, we hypothesized that BrCA and IR could affect PD1 and/or TIM3 expression on circulating CD8T. We determine PD1 and TIM3 expression on CD8T and analyze the relationship of CD8T phenotype with serum insulin and plasma adipocytokines levels in the different groups. We enrolled four groups of treatment-naive patients: women without neoplasms (Neo-)/without IR (IR-), Neo−/with IR (IR+), BrCa/ IR-and BrCa/IR+. We found interactions between BrCA and IR with respect to TIM3 on naïve and central memory (CM) CD8T subsets. Furthermore, BrCA had a greater PD1 + TIM3-CD8T frequency in CD8T subsets than Neo-. IR+ presented a significantly lower PD1 + TIM3-frequency in CD8T subsets compare to Non-IR. In addition, we found a negative correlation between insulin levels, HOMA and frequency of PD1 + TIM3-in CD8T and a positive correlation between adiponectin levels and the frequency PD1 + TIM3-in CD8T. The increased expression of PD1 on different subsets of CD8T from BrCa patients is consistent with immunological tolerance, whereas IR has a contrary effect. IR could have a deleterious role in the activation of CD8T that can be relevant to new BrCa immunotherapy.

Circulating T Cells Exhibit Different TIM3/Galectin-9 Expression in Patients with Obesity and Obesity-Related Diabetes

“…A recent study showed that TIM3 + CD8 + T cells may sustain the potential for IFN- γ production but lose cytotoxic activity in ovarian cancer [ 22 ]. Also, insulin resistance could induce the frequency of TIM3 expressing CD8 + T cells in breast cancer [ 23 ]. In our study, there was a significant increase in the TIM3 expression on CD8 + T cells in obese patients compared with HCs, and we found the positive correlation between TIM3 expression on CD8 + T cells and BMI, body fat percentage, and hip circumference.…”

High Dimensional Mass Cytometry Analysis Reveals Characteristics of the Immunosuppressive Microenvironment in Diffuse Astrocytomas

“…Specifically, the Treg proportion in the DA lesions was significantly increased in all patients (p < 0.05) ( Figure 3A). Programmed cell death protein 1 (PD-1)-, T cell immunoglobulin domain and mucin domain-3 (TIM-3)or lymphocyte activation gene 3 (LAG-3)-positive T cells are recognized as exhausted subsets (27)(28)(29). Compared to those in PBMCs, the proportions of TIM-3+ CD4+ T cells (p < 0.05) and PD-1+ CD8+ T cells (p < 0.01) were remarkably higher in tumor sites ( Figure 3A).…”

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary

“…Besides HLA-G and ILT-2, additional IC molecules such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and CD95 are associated in tumor-driven immune escape mechanisms acting locally at the tumor site or systemically in the peripheral blood (24)(25)(26). The continuous upregulation and co-expression of multiple IC, being often observed in cancer and chronic infections, are indicative for an immunosuppressive/exhausted phenotype of T cells and are associated with loss of effector functions and immunosurveillance (27,28).…”