Breast cancer patients have benefitted from a surge of new therapies in the last 15 years, bringing about a promising new era of personalized medicine where their diagnosis is less threatening than it was before. However, these improvements have uncovered a surprising trend: clinicians are now noting an increase in the number of patients who experience recurrent disease five or more years after their initial diagnosis. These “late recurrences” are attributed to a cell population called disseminated tumor cells, or DTCs, which “disseminate” or spread from the breast during earlier stages of disease. DTCs evade cancer killing drugs by dialing down the rate at which they divide and are also experts at avoiding recognition by immune cells. This results in a drawn-out game of hide-and-seek between the cancer cells and the ever-vigilant members of our immune system—a state referred to as tumor dormancy—which buys the DTCs time to find a suitable site to spread to and eventually create a new metastatic tumor.
However, just because DTCs can hide doesn’t mean that we can’t find them! This is the motto of Dr. Cyrus Ghajar, a clinician-scientist at Fred Hutch whose group recently published a study in Cancer Cell in collaboration with Dr. Stanley Riddell that employed immunotherapy to eradicate DTCs, bringing new hope that patients will be able to fight back against late disease recurrence. If the cancer cells are the villains of this story, then the hero (besides the members of Team Ghajar) must be the T cell, a hard-working member of the immune system whose job is to identify and remove anything that is considered foreign to the system. T cells are like antivirus software, constantly scanning files and programs to detect and eliminate anything harmful before it can cause damage. While antivirus programs rely on signature databases to recognize threats, T cells get their backup from Major Histocompatibility Complex I (MHC I), which is expressed on all our cells and presents peptides to T cells, enabling the immune system to recognize mutant or foreign peptides and target that specific cell. One of the reasons that DTCs are so good at hiding is that they ‘downregulate’ or decrease the amount of MHC I, disabling the mechanism by which T cells target mutated cells such as DTCs.
Ghajar and his team, spearheaded by postdoctoral fellows Dr. Erica Goddard and Dr. Miles Linde, set out to answer the following question: How do these cells escape immune surveillance, and can these methods be overcome to create curative therapies? The method that they used to answer this question makes use of one of biology’s most ubiquitous tools: Green Fluorescent Protein, or GFP. Ghajar’s team used GFP as a model antigen and found that DTCs persist despite functional immune responses and that, “Like others, we observe that single DTCs downregulate MHC I. But using a variety of approaches, we found that modulating class I levels did not enhance T cell recognition and killing of DTCs. Instead, we propose that DTC immune evasion is simply a numbers game. Because DTCs and antigen-specific T cells are so rare, they interact too infrequently to eliminate every single DTC.”
This phenomenon, termed “relative scarcity” by the authors, is compared in an editorial in Cancer Cell by postdoctoral fellow Anna Adam-Artigues to the Fermi paradox, which questions how it is that we have not managed to contact life forms from elsewhere in the universe and concludes that it is likely an issue of spatial separation. Adam-Antigues summarizes that “immune evasion by rare DTCs is mainly about large distances separating the low numbers of remnant DTCs and antigen-specific CD8+ T cells.” Fortunately, this groundbreaking work shows that residual DTCs can be targeted using methods that activate the adaptive immune system, such as adoptive T cell therapy or by engineering Chimeric Antigen Receptor T (CAR T) cells. CAR T cells are a synthetic T cell which can be designed in the lab to target an antigen expressed on the surface of the specific cell type. Think of it like a hunting dog which can be trained to smell for the scent of a certain kind of game, only in the human body with a CAR T cell hunting for disseminated tumor cells, and likely with less baying.
What followed was an intricate series of experiments using models of CD19 and HER2 as target-antigens where Goddard, Linde and colleagues demonstrate that CAR T cells almost completely eradicate DTCs in vivo, moving the dial from 78% of DTCs killed in distant tissues with a control T cell compared to 98.2% of DTCs killed with a targeted CAR T for CD19. Ghajar anticipates that “these findings will catalyze a search for high penetrance DTC-specific antigens and inspire T cell-based strategies to clear DTCs in patients.” The clinical relevance of this innovative research is confirmed by Adam-Antigues, who states that “this study provides a tantalizing possibility that increasing the dosage of effector CD8+ T cells would be sufficient to drastically reduce minimal residual disease.” Let the game of hide-and-seek begin!
Dr. Ghajar holds the Peter S. Lefkarites Memorial Endowed Chair.
Dr. Riddell hold the Burke O’Reilly Family Endowed Chair in Immunotherapy.
This work was supported by the Department of Defense (DoD) Breast Cancer Research Program, the National Breast Cancer Coalition’s Artemis Project (CMG), the National Institutes of Health, the Halt Cancer at X Foundation, the Mark Foundation for Cancer Research, and the Fred Hutchinson Cancer Center Cancer Consortium Support Grant.
Goddard, E. T., Linde M. H., Srivastava S., Klug G., Shabaneh T. B., Iannone S., Grzelak C. A., Marsh S., Riggio A. I., Shor R. E., Linde I. L., Guerrero M., Veatch J. R., Snyder A. G., Welm A. L., Riddell S. R., Ghajar C. M. (2024). Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies. Cancer Cell, Volume 42, Issue 1, 8 January 2024, Pages 119-134.e12.