Macrophage Polarization in Pembrolizumab Induced Mycobacterium Tuberculosis Granuloma Formation in Nasopharyngeal Carcinoma


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Tae Yang Desmond Hung1, Ngar Woon Kam1, Victor Ho Fun Lee1
1University of Hong Kong

Abstract

Background

Nasopharyngeal carcinoma (NPC) has a distinctive feature of high infiltration inflammatory cells, and the polarization of macrophages is a crucial prognostic factor. High infiltration of CD68+CD163- (M1-like macrophage) is associated with proinflammatory tumor microenvironment and disease-free survival, but CD163+ (M2-like macrophages) correlate with a poor prognosis in NPC. Different immunotherapy regimens are now actively investigated in treating NPC because of its unique tumor microenvironment, and pembrolizumab, an anti-programmed death-1(PD-1) immune checkpoint inhibitor, has shown promising results in early clinical trials. Intriguingly, various cases of pembrolizumab induced mycobacteria tuberculosis (MTB) activation/reactivation have been reported. MTB immunity heavily relies on macrophages. CD68+CD163- M1 is responsible for antimicrobial activity and granuloma formation, distinctive pathological feature of MTB infection, and CD163+ M2 is known to be responsible for tissue repairing. Our objective is to investigate the underlying mechanism of pembrolizumab induced MTB granuloma formation through understanding the macrophage polarization. 

Method

We collected biopsy samples from two NPC patients who suffered from pembrolizumab induced MTB. Their malignant, non-malignant and granuloma samples were collected and cut into 5┬Ám paraffin-embedded slides. The slides were stained with Opal multiplex immunohistochemistry staining kit and captured with Vectra Polaris.

Results

The cell density of CD68+CD163- M1 was the lowest in the non-malignant (79.3 cells/mm2), which was significantly lower than the granuloma group (961.5 cells/mm2, p=0.0027) and the malignant group (582 cells/mm2, p=0.0209).

The cell density changes of CD163+ M2 was relatively modest. The M2 cell density of the non-malignant group was also the lowest (835 cells/mm2), slightly lower than the granuloma group (1071 cells/mm2, p=0.58) and the malignant group.

Conclusion

Our results suggest that pembrolizumab might selectively polarize macrophages to CD68+CD163- M1 in the granuloma and malignant samples, but the effect on CD163+ M2 was relatively minimal. The induced M1 polarization might suggest that pembrolizumab could initiate proinflammatory microenvironment in NPC patients. Indeed, a similar effect on macrophages polarization was seen in non-small cell lung cancer. Since M1 macrophages were crucial for inducing granuloma formation, the pembrolizumab effect on macrophages polarization might provide a logical reasoning for triggering MTB granuloma formation.

Impact statement

Pembrolizumab treatment in NPC might induce M1 polarization and cause MTB granuloma.