When thinking about immune cells, an image forms where “defense” cells traffic to sites of infection and kill invading microbes. Dying cells at sites of infection signal to and recruit more and more immune cells, as seen by tissue inflammation. The other side of immune cell function is to balance the potency of inflammatory responses. Perhaps the best-studied immunosuppressive subsets of immune cells are T regulatory cells (Tregs). These cells keep the immune cells in check by limiting tissue damage during inflammatory responses as well as opposing autoimmune responses and contributing to immunosuppression in tumor microenvironments. To better understand the immune cell populations that differed between general inflammation and tumor microenvironments, the Prlic lab from the Fred Hutchinson Cancer Center employed single-cell analyses. From these studies, they discovered a specific sub-population of Tregs that was unique to the tumor tissues and therapeutically tractable. Work described herein was recently published in Nature.
The researchers first conducted single-cell analyses to define the immune cell populations in tumor tissues and general inflamed tissue. The tumor microenvironments were sampled from patients with head and neck carcinoma tumors and the non-malignant, inflamed microenvironment tissues were biopsied from patients undergoing oral surgery. The experimental design of these studies “provides a completely new view on the question [of] which immune phenotypes are truly unique to the human tumor microenvironment,” commented first author Dr. Florian Mair, currently a senior scientist in immunology at Kopf Laboratory ETH in Zurich, Switzerland.
Next, the researchers conducted comparative analyses and discovered that many immune cell populations within non-cancerous, inflamed tissues overlapped significantly with those that are present in tumor microenvironments. However, small differences were present. One specific divergence was noted, “a very large fraction of these critical Tregs in the tumor express the Interleukin-1 receptor type 1, and it turns out that this receptor marks the most immunosuppressive cells,” explained Dr. Mair. Interestingly, the tumor infiltrating Tregs also expressed a second receptor, ICOS, on their cell membrane that was not found on the Tregs present in the inflamed, non-cancerous tissues. Summarizing these findings, Dr. Mair stated, “we identified a new subset of immunosuppressive Tregs and two biomarkers that could be used for specific depletion of these cells from the tumor microenvironment.” Expanding on the significance of these findings Dr. Martin Prlic added, “all of a sudden, we now have a way of specifically targeting Tregs that only appear in tumors, and that is something that wasn’t possible before.”
This work characterizing immune cells of tumor versus inflamed tissue microenvironments provided a “map” of immune cell players at these two sites. To translate these findings into a therapy for head and neck cancers and possibly others, the researchers plan to develop a dual-specificity immunotherapy that will target the two unique proteins identified, IL1R1 and ICOS, on tumor-infiltrating Tregs. The researchers propose that this approach will specifically deplete the tumor-infiltrating immunosuppressive cells and allow other immune cells to mediate killing of cancer cells. Excitingly, the Washington Research Foundation has acknowledged these pioneering findings and recently awarded the Prlic team a phase II grant to develop a bi-specific antibody targeting Tregs which express both IL-1R1 and ICOS.
The spotlighted research was funded by the Emerson Collective, the Washington Research Foundation (WRF), the National Institutes of Health, and the FHCRC President’s Young Investigator Award.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Anthony Rongvaux, Brittany Barber, and Martin Prlic contributed to this work.
Mair F, Erickson JR, Frutoso M, Konecny AJ, Greene E, Voillet V, Maurice NJ, Rongvaux A, Dixon D, Barber B, Gottardo R, Prlic M. 2022. Extricating human tumour immune alterations from tissue inflammation. Nature. 605(7911):728-735.