Expansion of CMV-Mediated NKG2C+ NK Cells Associates with the Development of Specific De Novo Malignancies in Liver-Transplanted Patients

Abstract

Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV+ patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.

Transplantation-induced cancers: Emerging evidence that clonal CMV-specific NK cells are causal immunogenic factors

“…In this study, a hierarchical clustering of NK cell markers reveals that CMV infection is associated with the expansion of non-conventional fully differentiated NKG2A low CD62L low CD57 high NKG2C + “clonal” NK cells, whereas CMV - patients present a classical immature NKG2A high CD62L high CD57 low NKG2C - NK cells, as currently observed in immunocompromised patients 6 . The overall polyfunctionality of NK cells, measured by their capacities to degranulate and to produce cytokines such as interferon γ (IFNγ) and tumor necrosis factor α (TNFα), reveals that CMV-specific “clonal” NK cells produce large amount TNFα, 6 an inflammatory cytokine that plays a key role in the control and (or) the development of de novo tumors both in shaping adaptive T-cell responses and in enhancing inflammatory responses in tissues. In contrast, immature NK cells from CMV - patients mainly produced IFNγ, a cytokine that enhances adaptive T helper type 1 (Th1) responses.…”

“…Recently, we performed an extensive study of NK cells in patients after orthotopic liver transplantation (OLT), from the French K-GREF cohort, enrolled at the time of diagnosis for the development of de novo non-cutaneous tumors and compared with OLT patients without tumors 6 . In this study, a hierarchical clustering of NK cell markers reveals that CMV infection is associated with the expansion of non-conventional fully differentiated NKG2A low CD62L low CD57 high NKG2C + “clonal” NK cells, whereas CMV - patients present a classical immature NKG2A high CD62L high CD57 low NKG2C - NK cells, as currently observed in immunocompromised patients 6 .…”

“…The most intriguing result of our study was the exclusive development of de novo colorectal and head/neck tumors in patients with unconventional CMV-specific “clonal” NK cells, whereas, genitourinary tumors were only observed in CMV - patients with immature NK cells. In contrast, gynecological tumors and lymphoproliferative disorders were diagnosed in OLT patients, irrespective of their CMV status 6 . It is widely recognized that virus infection is implicated in several cancers in the general population, and also through study in patients with acquired immune dysfunction, such as those with AIDS.…”

Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans

“…1 NK cell proportion are associated with an increased risk of head/neck and colorectal tumours in liver transplant patients [49], which suggests that CMV may have divergent effects on NK cell cytotoxicity depending on the category of tumour. It is also important to determine how CMV infection and the proportion of NKG2C…”

Diversification of human NK cells: Lessons from deep profiling

“…Expansions of NKG2C + NK cells have also been reported in the context of immunodeficiency [134], organ transplantation [63,135–137], hantavirus infection [138], CHIKV infection [84], HIV-1 infection [139], and chronic HBV and HCV infection [107,140,141]. It remains unclear, however, if NKG2C + NK cell expansions induced by viruses other than HCMV are the result of a direct impact of the virus on NKG2C expression.…”