Bacteria residing within inside tumor cells can support malignant growth immunotherapy

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• Source: Weizmann Institute of Science


• Date: 22 Mar,2021

Cancer immunotherapy may get a boost from an unexpected direction: bacteria residing within tumor cells.

The study may also help clarify the connection between immunotherapy and the intestine microbiome, describing the findings of earlier research that the microbiome impacts the success of immunotherapy.

Immunotherapy remedies of the last decade or so have dramatically improved healing rates from certain cancers, particularly malignant melanoma; however in melanoma, they still work in just about 40 percent of the cases.

Prof. Yardena Samuels of Weizmann’s Molecular Cell Biology Department studies molecular”signposts” – protein fragments, or peptides, on the cell surface – which indicate cancer cells as foreign and may therefore serve as potential additional targets for immunotherapy. In the new study, she and colleagues extended their search for new cancer signposts to all those bacteria known to purge tumors.

Using methods developed by departmental colleague Dr. Ravid Straussman, that was one of the first to reveal the essence of the bacterial”guests” in cancer cells, Samuels and her group, led by Dr. Shelly Kalaora and Adi Nagler (joint co-first authors), analyzed tissue samples from 17 metastatic melanoma tumors derived from nine patients. They obtained bacterial genomic profiles of these tumors and then implemented an approach known as HLA-peptidomics to recognize tumor peptides that may be recognized by the immune system.

The research was conducted in collaboration with Dr. Jennifer A. Wargo of the University of Texas MD Anderson Cancer Center, Houston, Texas; Prof Scott N. Peterson of Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; Prof Eytan Ruppin of the National Cancer Institute, USA; Prof Arie Admon of the Technion – Israel Institute of Technology and other scientists.

The HLA peptidomics analysis revealed nearly 300 peptides from 41 different bacteria on the surface of the melanoma cells. The crucial new finding was that the peptides were displayed on the cancer cell membranes by HLA protein complexes – complexes that are present on the membranes of all cells in our body and play a role in regulating the immune response.

Among the HLA’s jobs is to sound an alarm about whatever’s foreign by”introducing” foreign peptides to the immune system so that immune T cells can”see” them. “Using HLA peptidomics, we were able to reveal the HLA-presented peptides of the tumor in an unbiased fashion,” Kalaora says. “This method has already enabled us in the past to identify tumor antigens which have shown promising results in clinical trials.”

It’s unclear why cancer cells ought to carry out a seemingly suicidal act of this sort: presenting bacterial peptides to the immune system, which can react by destroying cells. However, whatever the reason, the fact that cancerous cells do display these peptides in this manner shows an entirely new kind of interaction between the immune system and the tumor.

This revelation supplies a potential explanation for how the gut microbiome impacts immunotherapy. Some of the germs the team identified were known gut microbes. The presentation of the bacterial peptides on the surface of tumor cells is likely to play a role in the immune response, and future studies may establish that bacterial peptides improve that immune response, allowing physicians to predict the success of immunotherapy and to tailor a personalized treatment accordingly.

Moreover, the fact that bacterial peptides on tumor cells are visible to the immune system may be exploited for improving immunotherapy. “Many of these peptides were shared by different metastases from the same individual or from tumors from different patients, which suggests that they have a therapeutic potential and a potent ability to generate immune activation,” Nagler says.

In some experiments that were continuing, Samuels and colleagues incubated T cells from melanoma patients at a laboratory dish together with bacterial peptides derived from tumor cells of the same patient. The result: T cells were activated specifically toward the bacterial peptides.

Our findings suggest that bacterial peptides presented on tumor cells can serve as potential targets for immunotherapy. They may be exploited to help immune T cells recognize the tumor with greater precision, so that these cells can mount a better attack against the cancer. This approach can in the future be used in combination with existing immunotherapy drugs.”

Yardena Samuels, Professor, Molecular Cell Biology Department, Weizmann Institute of Science