Previous work has laid the foundation by establishing a role for the microbiome in cancer patients’ responses to some immunotherapy treatments. Part of this was the understanding that some bacteria are known to colonize human tumors, proliferate within them, and modulate immune function. But many questions remain regarding the underlying mechanism involved in this process.

Researchers at the Weizmann Institute of Science and their collaborators have discovered that the immune system recognizes the bacteria in the tumor, and that they can be harnessed to provoke an immune reaction against the tumor. The study may also help clarify the connection between immunotherapy and the gut microbiome, explaining the findings of previous research that the microbiome affects the success of immunotherapy.

This research is published in Nature in the article, “Identification of bacteria-derived HLA-bound peptides in melanoma.

Immunotherapy treatments of the past decade or so have dramatically improved recovery rates from certain cancers, particularly malignant melanoma; but in melanoma, they still work in only about 40% of the cases. Yardena Samuels, PhD, associate professor, molecular & cell biology department, Weizmann Institute, Israel, senior author on the paper, studies molecular “signposts”—protein fragments, or peptides, on the cell surface—that mark cancer cells as foreign and may therefore serve as potential added targets for immunotherapy. In the new study, she and colleagues extended their search for new cancer signposts to those bacteria known to colonize tumors.

Using methods developed by Ravid Straussman, MD, PhD, who previously showed that bacteria reside in cancer cells, Samuels and members of her lab, led by Shelly Kalaora, PhD, and Adi Nagler, a graduate student in the lab, analyzed tissue samples from 17 metastatic melanoma tumors derived from nine patients. They obtained bacterial genomic profiles of these tumors with 16S rRNA gene sequencing and then applied an approach known as HLA-peptidomics to identify tumor peptides that can be recognized by the immune system.

The authors noted that it is not known whether antigens derived from intracellular bacteria are presented by the HLA-I and HLA-II molecules of tumor cells, or “whether such antigens elicit a tumor-infiltrating T-cell immune response.”

Their goal was to, “identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumors.”

The HLA peptidomics analysis revealed 248 peptides (35 unique) 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 surfaces by HLA protein complexes.

“Using HLA peptidomics, we were able to reveal the HLA-presented peptides of the tumor in an unbiased manner,” Kalaora said. “This method has already enabled us in the past to identify tumor antigens that have shown promising results in clinical trials.”

It’s unclear why cancer cells should perform a seemingly suicidal act of this sort: presenting bacterial peptides to the immune system, which can respond by destroying these cells. But the fact that malignant cells do display these peptides in such a manner reveals an entirely new type of interaction between the immune system and the tumor.

This revelation supplies a potential explanation for how the gut microbiome affects immunotherapy. Some of the bacteria 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 which bacterial peptides enhance that immune response, enabling 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 can be exploited for enhancing immunotherapy. “Many of these peptides were shared by different metastases from the same patient or by tumors from different patients, which suggests that they have a therapeutic potential and a potent ability to produce immune activation,” Nagler said.

In a series of continuing experiments, Samuels and colleagues incubated T cells from melanoma patients in 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,” Samuels said. “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.”

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