Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors which may represent ideal targets for immunotherapy. Using high throughput immunologic screening of mutant gene products identified via whole exome sequencing, we identified neoantigen reactive tumor infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic non-synonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell based immunotherapies for patients bearing these cancers.
Myeloid cells, including granulocytes, monocytes, macrophages and dendritic cells, are crucial players in innate immunity and inflammation. These cells constitutively or inducibly express a number of receptors of the TNF receptor and Toll-like receptor (TLR) families, whose signals are transduced by TRAF molecules. In vitro studies showed that TRAF3 is required for TLR-induced type I interferon production, but the in vivo function of TRAF3 in myeloid cells remains unknown. Here we report the generation and characterization of myeloid cell-specific TRAF3-deficient (M-TRAF3−/−) mice, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-κB2 activation. However, in response to injections with LPS (a bacterial mimic) or polyI:C (a viral mimic), M-TRAF3−/− mice exhibited an altered profile of cytokine production. M-TRAF3−/− mice immunized with T cell-independent (TI) and -dependent (TD) antigens displayed elevated TI IgG3 as well as TD IgG2b responses. Interestingly, 15–22 month old M-TRAF3−/− mice spontaneously developed chronic inflammation or tumors, often affecting multiple organs. Taken together, our findings indicate that TRAF3 expressed in myeloid cells regulates immune responses in myeloid cells and acts to inhibit inflammation and tumor development in mice.
Microglia, the resident immune cells of the brain, perform elaborate surveillance in which they physically interact with neuronal elements. A novel form of microglia–neuron interaction named microglial process convergence (MPC) toward neuronal axons and dendrites has recently been described. However, the molecular regulators and pathological relevance of MPC have not been explored. Here, using high-resolution two-photon imaging in vivo and ex vivo, we observed a dramatic increase in MPCs after kainic acid– or pilocarpine-induced experimental seizures that was reconstituted after glutamate treatment in slices from mice. Interestingly, a deficiency of the fractalkine receptor (CX3CR1) decreased MPCs, whereas fractalkine (CX3CL1) treatment increased MPCs, suggesting that fractalkine signaling is a critical regulator of these microglia–neuron interactions. Furthermore, we found that interleukin-1β was necessary and sufficient to trigger CX3CR1-dependent MPCs. Finally, we show that a deficiency in fractalkine signaling corresponds with increased seizure phenotypes. Together, our results identify the neuroglial CX3CL1–CX3CR1 communication axis as a modulator of potentially neuroprotective microglia–neuron physical interactions during conditions of neuronal hyperactivity.
Increasing evidence indicates that TRAF molecules are versatile and indispensable regulators of inflammation and inflammatory responses and that aberrant expression or function of TRAFs contributes to the pathogenesis of inflammatory diseases.
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