BCG Impact on PD-1/PD-L1 Expression in Peripheral Immunocytes of Cancer Patients—A Potential Explanation for Its Activity in Preventing Alzheimer’s Disease

We found, retrospectively, that BCG therapy in non-muscle invasive bladder cancer (NMIBC) reduces the rate of Alzheimer’s disease. Blockade of the ligand PD-L1 or its checkpoint receptor PD-1 has been shown to improve cognitive function and reduce brain pathology features in a mouse model of Alzheimer’s disease (AD). Given that peripheral blood mononuclear cells (PBMCs) are involved in aging brain pathology and thus represent a potential AD therapeutic target, we analyzed the impact of BCG on the expression of PD-1, PD-L1, and inflammation modulators in PBMCs. Cryopreserved PBMCs pre- and post-BCG-treated six melanoma and six NMIBC patients were repurposed for immunoelectrophoretic analysis of PBMC-extracted proteins. PBMCs, post-BCG treatment in melanoma patients, were harvested only 4 months after the start of treatment (short BCG period), whereas the PBMCs of NMIBC patients were harvested 24 to 52 months after starting the BCG treatment. In melanoma PBMCs, BCG upregulated PD-L1 (p = 0.052) while downregulating PD-1 (insignificantly, p = 0.16). In contrast, in NMIBC patients, BCG downregulated PD-L1 (insignificantly, p = 0.67), while upregulating PD-1 (p = 0.0082). PD-L1 positive correlation with p-IkB (r = 0.7228) under BCG is inverted to that of PD-L1 against IkB (p = −0.9491). The difference between these opposite correlations is significant (p = 0.011), indicating that PD-L1 is upregulated early after BCG treatment, in association with p-IKB, which enables inflammation. This association subsided later, and for PD-1, did not occur at the short or long BCG periods. Experiments with a larger number of patients may substantiate the hypothesis that an increase in PD-1 by BCG relative to PD-L1 may protect against AD.