PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Abstract

Boosting immune cell function by targeting the coinhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here, we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with anti–PD-1 monoclonal antibody developed worse disease and higher granuloma bacterial loads compared with isotype control–treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in anti–PD-1–treated macaques were not increased in number or function in granulomas, expressed increased levels of CTLA-4, and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of anti–PD-1–treated animals, multiple proinflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Last, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota before infection in individual macaques. Therefore, PD-1–mediated coinhibition is required for control of Mtb infection in macaques, perhaps because of its role in dampening detrimental inflammation and allowing for normal CD4 T cell responses.

Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung

“…Although we do not find evidence for a protective role for IFN-γ and TNF-α in this study, a wealth of data indicates that complete loss of the cytokines renders both animals and humans highly susceptible of Mtb (7). Conversely, elegant studies in mice and NHP from Dan Barber's group show that the loss of immune control in the lung associated with interference in the PD-1 immune checkpoint axis is directly related to excessive production of IFN-γ and TNF-α (most recently (74)). Thus, whilst these data and a growing number of studies suggest an important role for IL-17 in the immune response to Mtb, it is highly likely that a balanced immune response is still required (75).…”

“…Conversely, elegant studies in mice and NHPs from Dan Barber’s group show that the loss of immune control in the lung associated with interference in the PD-1 immune checkpoint axis is directly related to excessive production of IFN-γ and TNF-α (most recently ref. 74 ). Thus, although these data and a growing number of studies suggest an important role for IL-17 in the immune response to M .…”

Clinical and immunologic implications of COVID-19 in patients with melanoma and renal cell carcinoma receiving immune checkpoint inhibitors

“…Therefore, the timing of PD-1 blockade may pose a modulatory role in host immune responses that warrants further exploration within the clinical setting. [72][73][74] Lastly, evidence remains limited when attempting to define and understand the immunologic aberrancies associated with ICI treatment throughout a COVID-19 infection. 24 75-78 Several hypotheses regarding the clinically detrimental effects of ICIs in patients infected with COVID-19 are currently under investigation.…”

“…136 In addition, although the presence of PD-1 is known to enhance CD8+ T-cell exhaustion during chronic infection and cancer, 137 the exact timing of PD-1 blockade during CD8+ T-cell differentiation in the setting of an acute viral infection, as outlined in section III, may pose a modulatory role in host immune responses. [72][73][74] Such observations, although compelling given the theoretic implications of suboptimal long-term T-cell memory or variable immune responses on vaccination in ICI-treated patients, require further study within the clinical setting.…”

Advancing Adjuvants for Mycobacterium tuberculosis Therapeutics

“…Developing adjuvants that target additional immune evasion pathways in DCs, such as autophagy, can enhance antigen presentation (93). Targeting costimulatory and coinhibitory molecules on DCs has the potential to be beneficial in improving the immunogenicity of candidate vaccine by fine-tuning the pro-and anti-inflammatory pathways necessary for optimal immunity (91,(161)(162)(163). Additionally, adjuvants that limit early induction of IL-10 and T-regulatory cell expansion may be effective given the role of these responses in dampening immune responses during infection (164)(165)(166).…”