Nature. The mechanism by which autophagy promotes immune escape for pancreatic cancer.

The immune escape of zhangtailiu is a major problem in tumor treatment. The common escape mechanisms include MHC-I mutation or loss of heterozygosity, which results in the damage of antigen presentation process and the resistance of immune checkpoint blocking therapy (ICB) [1].pancreatic ductal adenocarcinoma (PDAC) is resistant to the treatment of most tumors such as ICB. Although mutations leading to loss of MHC-I rarely occur in PDAC, the expression of MHC-I is often down regulated [2].however, the mechanism of MHC-I down-regulation in PDAC is still unclear.recently, from the University of California, San Francisco RushikaM.Perera Collaboration with Alec C C. Kimmelman of New York University School of medicine in nature In PDAC, we report that nbr1, an autophagic cargo receptor protein, targets and selects MHC-I molecules on the cell surface and downregulates MHC-I through autophagy dependent lysosomal degradation pathway. The MHC-I of PDAC was mainly located on autophagosome and lysosome, but the expression of MHC-I on cell surface was decreased.inhibition of autophagy can restore the level of MHC-I on cell surface, increase antigen presentation, increase anti-tumor T cell response, and reduce tumor growth in mice; moreover, the anti-tumor effect of inhibition of autophagy depends on the expression of MHC-I on CD8 + T cells and cell surface.combination of anti-pd1 + anti-CTLA4 resulted in significantly enhanced anti-tumor immune response.the researchers first found that the total MHC-I protein level in human PDAC cell lines was heterogeneous, and there was a significant point cytoplasmic distribution of MHC-I and lysosome co localization.however, MHC-I molecules were mainly located in the cell membrane in the untransformed human pancreatic ductal epithelial (HPDE) cells. Compared with HPDE lysosomes, MHC-I molecules were highly enriched on PDAC lysosomes.lysosomal inhibition leads to the accumulation of MHC-I in lysosomes, which indicates that MHC-I reaches lysosome for degradation.most of the MHC-I spots were Co located with lc3b labeled autophagy bodies, which was consistent with the increase of autophagy in PDAC.in addition, the localization of MHC-I in most PDAC cell lines and all human PDAC tumors was detected.knockdown of atg3 and ATF7 inhibition of autophagy or inhibition of lysosome by bafa1 inhibitor of V-ATPase could increase the total MHC-I level and MHC-I level of cell membrane in PDAC cells, and bafa1 or chloroquine inhibited lysosome did not affect other proteins involved in antigen processing and presentation.autophagy cargo receptor proteins bind and recruit substrates to the membrane of autophagy bodies, thus realizing the selective degradation of targeted molecules by autophagy.the researchers screened the autophagic receptor proteins of PDAC mediated MHC-I degradation, and found that only nbr1 interacted with MHC-I.immunofluorescence showed that nbr1 and MHC-I Co located more frequently in PDAC than in HPDE cells.nbr1 interacts with ubiquitinated substrates and mediates its degradation, while MHC-I in PDAC is polyubiquitinated. Furthermore, nbr1 knockdown resulted in the increase of total MHC-I and membrane MHC-I in PDAC, i.e., the decrease of MHC-I on PDAC cell surface was mediated by nbr1 mediated autophagy lysosomal degradation pathway.in addition, the basic autophagy level in PDAC cells affected their immunogenicity. The ability of PDAC cells with low autophagy level was decreased, and the tumor formation was smaller, and the expression of MHC-I was higher, and the tumor infiltrated CD8 + T cells more. CD8 + T cells play an anti-tumor immune response by recognizing the antigen presented by MHC-I of tumor cells. Does the decrease of MHC-I on the surface of PDAC help them escape the killing of CD8 + T cells and thus have resistance to most tumor treatments? The researchers constructed a PDAC cell line with inducible autophagy inhibition, and found that autophagy inhibition led to the increase of MHC-I on cell surface and antigen peptide presentation. in PDAC cells, induced autophagy inhibition increased the proliferation of co cultured CD8 + T cells, increased the expression of IFN - γ and TNF, and decreased the activity of PDAC. in situ tumor model and metastatic tumor model of mice, autophagy inhibited cells had smaller tumor formation, higher MHC-I expression, no change in PD-L1 expression, increased CD8 + T cell infiltration and decreased myeloid derived heterogeneous cells. CD103 + DC cells play an important role in the activation and recruitment of CD8 + T cells. at the same time, autophagy inhibited the loss of MHC-I in tumor cells, resulting in the decrease of CD8 + T cells and the recovery of tumor growth. PDAC was resistant to tumor therapy, while the PDAC with autophagy inhibition responded well to double ICB therapy (anti-pd1 + anti-CTLA4), and the infiltration of CD8 + T cells and PD1 + tim3 - cells increased, which means that inhibition of autophagy in tumor cells can improve the sensitivity of PDAC to double ICB. then, does the combination of inhibition of autophagy and dual ICB have clinical transformation potential? Chloroquine can inhibit the process of lysosomal acidification. It is a clinically available drug for systemic inhibition of autophagy. chloroquine can increase the surface MHC-I level of mouse PDAC tumor, but can not control the tumor growth. The combination of chloroquine and double ICB can induce strong anti-tumor immunity, decrease autophagy and increase CD8 + T cell infiltration. that is, whether tumor cells alone or systemic autophagy inhibition can improve the sensitivity of PDAC tumors to dual ICB therapy. in general, studies have demonstrated that autophagy or lysosome function enhancement in PDAC can achieve immune escape by selectively targeting MHC-I molecular degradation, revealing a new therapeutic strategy of autophagy inhibition combined with double ICB therapy or PDAC. In this paper, the author of this paper is a brief introduction to the development of the Chinese Journal of science and technology, N. Loss of expression of antigen-presenting molecules in human pancreatic cancer and pancreatic cancer cell lines. Clin. Exp. Immunol. 148, 127–135 (2007).