Science: the dark side of autophagy helps cancer cells escape from the immune system

The rise of tumor immunotherapy has brought a new dawn for human beings to conquer the “king of all diseases” – cancer. Among them, immune checkpoint blocking therapy has become one of the most popular immunotherapies, which has significantly changed the current pattern of cancer treatment, and PD-1 / PD-L1 immunoblocking therapy is the most typical representative. < / P > < p > although tumor immunotherapy has significantly changed the pattern of cancer treatment, there are still a large number of patients who do not respond to these therapies due to a variety of reasons. Therefore, we need to further understand the molecular mechanism of T cell killing sensitivity of tumor cells. < / P > < p > autophagy is an evolutionarily conserved lysosome mediated biodegradation process, which is the recycling of cell waste and plays an important role in regulating cell homeostasis. Therefore, autophagy is closely related to a variety of diseases. < / P > < p > using CRISPR screening technology, the researchers found that knockout of an autophagy related gene named rb1cc1 can increase the killing sensitivity of tumor cells to T cells, thus enhancing the anticancer effect of PD-1 and CTLA-4 checkpoint inhibitors. These findings suggest a new role of autophagy in cancer, and open up a new direction for the use of autophagy inhibitors to improve the effect of tumor immunotherapy in more patients. < / P > < p > in order to identify the genes that regulate the sensitivity of tumor cells to T cell-mediated killing, the research team conducted a genome-wide CRISPR / cas9 screening in mouse colon adenocarcinoma cells. The results of < / P > < p > experiment show that TNF – α plays a key role in tumor cell death, which is consistent with previous studies. In contrast, autophagy in tumor cells seems to protect them from T-cell-mediated death. The knockout of three key autophagy genes rb1cc1, atg9a and atg12 by the research team can significantly increase the killing sensitivity of tumor cells to T cells. < / P > < p > the research team further found that blocking TNF – α and knocking out rb1cc1 gene with antibody had very limited effect on killing tumor cells, which indicated that the protective effect of autophagy on tumor cells was mainly mediated by TNF – α pathway. < / P > < p > the research team further tested this discovery in a mouse model of breast cancer. Similarly, knockout of rb1cc1 gene can increase the lethality of breast cancer cells. < / P > < p > the research team used the combination of PD-1 antibody and CTLA-4 antibody to treat the mouse model of breast cancer. The results showed that the combination antibody completely eliminated the tumor cells with rb1cc1 gene knockout, but only moderately inhibited the growth of the control tumor cells. Similar results were observed in the colon cancer model. < / P > < p > the data also show that, even in tumor cells with rb1cc1 gene knockout, simultaneously knockout of TNF – α receptor limits the anticancer effect of immunotherapy, which indicates that TNF – α and autophagy are indeed essential for T cells to kill tumor cells. < / P > < p > through CRISPR screening, the research team screened six kinds of mouse tumor cells including breast cancer, colorectal cancer, renal cancer and melanoma, and successfully identified 182 “core cancer innate immune escape genes”. The deletion of these genes makes cancer cells more sensitive or more resistant to T cell attack. This study successfully mapped cancer immune escape genes. This study found that knockout of atg12 and ATG5 at the same time can help tumor cells resist T cell killing, but knockout of only one of them has no such effect. Details: in general, the research of Zaiyuan company shows that targeting autophagy pathway may be a promising strategy to enhance the killing ability of T-cell immunotherapy on tumor, which is expected to help more cancer patients benefit from powerful cancer immunotherapy drugs. Continue ReadingIqoo5 series debut strength interpretation of “120 super full mark flagship”