Tumor MHC class I expression alters cancer-associated myelopoiesis driven by host NK cells

Abstract

Downregulation of MHC class I (MHCI) molecules on tumor cells is recognized as a resistance mechanism of cancer immunotherapy. Given that MHCI molecules are potent regulators of immune responses, we postulated that the expression of MHCI by tumor cells influences systemic immune responses. Accordingly, mice-bearing MHCI-deficient tumor cells showed reduced tumor-associated extramedullary myelopoiesis in the spleen. Depletion of natural killer (NK) cells abrogated these differences, suggesting an integral role of immune-regulatory NK cells during tumor progression. Cytokine-profiling revealed an upregulation of TNF-α by NK cells in tumors and spleen in mice-bearing MHCI expressing tumors, and inhibition of TNF-α enhanced host myelopoiesis in mice receiving adoptive transfer of tumor-experienced NK cells. Our study highlights a critical role of NK cells beyond its identity as a killer lymphocyte and more importantly, the potential host responses to a localized tumor as determined by its MHCI expression.

Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis

“…However, the underlying trigger that initiates the production of IL-6 by NK cells remains unknown. Recent studies revealed that defective NK cell cytotoxicity is associated with the increased production of inflammatory cytokines (61)(62)(63). Still, the underlying cellular biology in which cytokine production is mechanistically influenced by NK cell-killing capacity remains elusive.…”

“…Consistent with our b2m -KO tumor models, Bunting et al ( 62 ) demonstrated that MHCI expression in melanoma is associated with the deposition of extracellular proteins that dampen NK cell–killing capacities and promote their production of inflammatory cytokines. NK cells within MHCI-deficient RMA-S lymphoma tumors were also found to produce higher amounts of IFN-γ ( 63 ). By either knocking out B2M in murine tumor cells or depleting the host NK cells, the frequencies of M-MDSCs in the tumors were also reduced.…”

“…From our transcriptomics analysis, tumor-experienced NK cells showed higher expression of EBI3 , which encodes IL-35 and is known to cause accumulation of MDSCs and subsequent tumor angiogenesis ( 66 ). Moreover, higher frequencies of GM-CSF and TNFα-producing NK cells were observed in RMA tumors ( 63 ).…”

“…SNU-475 [American Type Culture Collection (ATCC)], HUH7 (Japanese Collection of Research Bioresources, JCRB), RMA, RMA-S, and B16F10 (ATCC) were maintained in RPMI supplemented with 10% FBS. The generation of B16F10, 4T1, and MC38 cells with a knockout of B2M was established as previously described ( 63 ). The list of purchased inhibitors with their respective experimental purposes is provided in table S5.…”

Efficacy and safety of chemoimmunotherapy in advanced non-small cell lung cancer patients with antibiotics-induced dysbiosis: a propensity-matched real-world analysis

“…The impact of gut microbiota on tumor immunity is similar to that of irAEs in terms of antigenicity. It is noteworthy that the administration of antibiotics before IOs has been shown to disrupt the gut microbiota and subsequently reduce the incidence of irAEs (Kostine et al 2021 ; Neo et al 2022 ). Certain bacterial species, such as Bacteroides spp.…”