Nat Commun: A key molecule in the immune escape of autophagy defects in tri-yin breast cancer.

Triple Negative Breast Cancer( TNBC) remains a cancer treatment challenge.
previous studies have shown that TNBC subsysmectors are more immunogenic than breast cancer patients with Luminal A/B sub-type or HER-plus sub-type, indicating that TNBC patients are more likely to benefit from immunotherapy, but immunosepologic inhibitors PD-1 and PD-L1 monotherapy are less effective against single-drug drugs for tricycosis breast cancer.
that in the process of interaction between sanyin breast cancer cells and the micro-environment, there are many factors that restrict the lethal effect of activated T cells on tumors.
and intervention of these constraints can greatly improve the efficacy of T-cell immunotherapy for the benefit of patients.
autophagy, an evolutionaryly relatively conservative form of protein degradation that degrades proteins and cytoplasm with long half-lifes, runs through the evolution of breast cancer.
how this mechanism activates or limits attacks on tumor cells by T-lymphocytes in the immune system is still not well understood.
In previous studies, the Zhu Xiaofeng Research Group and the Foreign Research Group of Sun Yat-sen University Cancer Prevention and Control Center have reported low protein expression levels in breast cancer of autophagy genes ULK1 and Beclin 1, respectively, and the low level of Beclin 1 mRNA can be an independent predictive indicator for TNBC patients.
Thus, to some extent, even if external factors induce breast cancer cells to autophagy, their ability to autophagy is relatively low, a phenomenon that may be more pronounced in TNBC patients.
to explore the role of autophagy in T-cell attacks on three-yin breast cancer cells, the authors conducted a series of studies.
Recently, Sun Yat-sen University Cancer Prevention Center Deng Wei/Zhu Xiaofeng/Tang Jun collaborated on the results of a study published in Nature Communications entitled Autothagy Information Promotes Triple Negative-Negative Breast Cancer Resistance to T Cell-Mediated Cytoxicity by Blocking Tenascin-C Solution.
The study reveals that autophagy defects play an important role in the realization of escape T-cell immune attack in sanyin breast cancer cells, and identifies Tenascin C as a key target for T-cell immune tolerance caused by autophagy defects, providing a new treatment strategy for the immune tolerance of sanyocym breast cancer.
the study first identified the tolerance of TNBC cells with autophagy defects to T-cell immunity.
The authors used CRISPR-Cas9 or RNAi techniques to knock out or interfere with the expression of autophagy-related genes such as Atg5, Atg7, and Beclin 1, and constructed tNBC cell models of autophagy defects and mouse transplant tumor models to observe the lethal effects of activated T lymphocytes on autophagy of different tumor cells.
the results showed that TNBC cells with autophagy defects were able to escape the immune attack of T cells, and observed a significant increase in the tumor-inging ability of autophagy-defective 4T1 tumor cells, and a significant decrease in the number and activity of immersive T-cells.
data analysis on the Tumor Immune Information Resource (TIMER) website also showed that mRNA expressions of Atg5 and Beclin 1 were only positively associated with the immersion of TIL cells in Basal-like breast cancer.
In order to find immunosuppressive molecules associated with autophagy defects, the authors combined SILAC protein labeling techniques with GSEA paths to analyze protein expression differences in wild and autophagy defect tumour cells, using gene optimization principles to screen out the autophagy-regulated key immunosuppressive molecular extracellular substational protein Tenascin-C (TNC).
Further studies confirmed a significant increase in TNC protein levels in TNBC cells with autophagy defects, a significant increase in TNC protein levels;
next, the authors shed light on the molecular mechanisms by which TNC proteins express highly in autophagy-defective TNBC cells.
autophagy lysogen pathway is one of the important degradation pathways of ethyl cells.
the relationship between abnormal pathways of selective autophagy-lysogen degradation and tumors has been reported.
study, the authors found that hunger-induced autophagy significantly reduced TNC protein levels in wild TNBC cells, but that TNC degradation in autophagy-defective cells was blocked.
suggests that TNC may be degraded by autophagy lysogen.
further studies have shown that E3 Ubiquitin-Linked Protein Skp2 can mediat K63-type ubiquitin markers at Lys942 and Lys1882 sites of TNC protein, prompting the TNC protein to bind within cells through its FN3 domain and the UBI uba (Ubiquitin-Associated Binding domain) of autophagy receptolate protein P62.
Then the receptoned protein P62 on the one hand to degrade the substrate protein TNC to the vicinity of autophagy bubbles, on the other hand, through its LIR (LC3-interacting region) base sequence and autophagy on the ATG8/LC3 binding, so that TNC is finally selectively degraded in the lysophagic.
in TNBC cells with autophagy defects, TNC proteins are significantly higher in expression because they cannot degrade through selective autophagy-lysogen pathways.
because most TNBC patients are ineffective or insensitive to immunoseamide inhibitors, it is important to propose new immuno-combined therapy strategies.
based on the above experiments, the authors speculate that autophagy defects of TNBC cells with high expression of TNC may inhibit the efficacy of immunosepm inhibitors.
the author first made a series of letter analysis and immunogroup analysis to further clarify the clinical application value of TNC.
using the KM plotter database, the authors found that in ER-breast cancer patients, especially in basal-like patients, TNC's mRNA level was high expression, with no recurrence (RFS), total survival (OS), no distant metastasis survival (DMFS), and lower post-progress survival (PPS).
further immuno-histification analysis showed that TNC protein high expression was an independent prognostic factor in TNBC patients, and was negatively related to LC3B expression, and significantly negatively related to CD8-T cell tumor immersion.
the authors then used immunos checkpoint inhibitors and targeted TNC treatments on the autophagy-defect TNBC cell model and the mouse transplant tumor model.
results showed that TNC monoanti and anti-PDL1 were significantly more lethal to autophagy defect TNBC cells than single drugs, and induced knock-down TNC was found to enhance the therapeutic effect of PD1 monoantigenic on autophagy defect 4T1 transplant tumor.
overall, the study explores how to improve TNBC patients' responses to T-cell immunotherapy from the perspective of autophagy, providing a new perspective for studying the interaction between tumor autophagy and the immune microunit environment.
the study also identified the efficacy of targeting TNC to enhance the efficacy of immunoseptive inhibitors on autophagy-defective tumors, providing TNBC patients with promising therapeutic strategies.
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