Inhibiting PD-1 Restores Mycobacterium Tuberculosis Specific Poly-functional T Cells: Impact on Therapy of Drug Resistant Tuberculosis Patients

Abstract Rationale: Previously, we demonstrated the critical role of regulatory T (Treg) cells and PD-1 pathway in suppression of T cell response against Mycobacterium tuberculosis (M.tb) among tuberculosis (TB) patients. Here, we checked the status of host immune response among the drug resistant (DR) and Drug Sensitive (DS) tuberculosis (TB) patients. Additionally, in a phase I/ II clinical trial, we investigated impact of in vivo inhibition of PD-1 pathway on rescuing effector T cell function in TB patients. Methods: For immune profiling and in vitro experiments, polychromatic flow cytometry-based assays were performed. A phase-I/ II clinical trial was initiated among TB patients, with injection of Nivolumab at two different doses (0.5 mg / kg & 1 mg/ kg) at 3 time points during the intensive phase of anti-tubercular treatment. The sputum conversion and immune profile of patients were carefully monitored during intensive phase. Results: Among DR-TB patients, we observed an increase in the frequency of Tregs and decrease in frequency of Mtb specific T cells (IFN-γ+ /TNF-α+) compared to DS TB patients. Furthermore, we observed modulation of efflux pumps of M.tb by pro-inflammatory (IFN-γ, TNF-α) and anti-inflammatory cytokines (IL-10 and TGF-β) in the in vitro Monocyte Derived Macrophag infection model.In our clinical trial, we observed a faster recovery of poly-functional T cells (PFTs, CD4+ IFN[[Unsupported Character – Symbol Font γ]]+ TNF[[Unsupported Character – Symbol Font α]]+) than the control group. In DS patients, sputum conversion rate at the end of intensive phase (2 months) in the intervention group (1 mg/kg dose of Nivolumab) was 87.5%, higher than that in the control group (70%). Interestingly, in DR patients, at the end of two months, the sputum conversion rate in the intervention group (both 0.5 mg/kg and 1 mg/kg dose) was 70%, markedly higher than the control group (50%). Conclusions: Our findings suggest the critical role of PD-1 in dampening the protective immune response in TB patients. Rescuing PFTs by blocking the PD-1 pathway may offer a novel strategy for adjunct immunotherapy in TB. This may be more relevant in DR-TB by down regulating the efflux pumps, which may increase drug accumulation, so as to effectively clear the bacilli. Therefore, inhibiting PD-1 pathway may improve the efficacy of anti-tubercular therapy, for DR-TB in terms of immune recovery and early sputum conversion. If substantiated, anti PD-1 based adjunct immunotherapy in DR-TB treatment may have significant impact on the epidemiology of disease transmission.