New insights into T cell function in multiple myeloma patients

Despite improvements in therapies, multiple myeloma (MM) is a disease that will always relapse. Why is this? What is the key to finding effective therapies to cure MM? Evan Newell, a Professor in the Vaccine and Infectious Disease Division at Fred Hutch Cancer Center, posited that studying T cells in newly diagnosed MM patients may provide some insight into this knowledge gap. T cells can have a mighty role when it comes to targeting cancer cells and inducing cell killing (e.g. CAR T-cell therapy). However, in some cases, T cell dysfunction limits antitumoral activity. For example, in some patients, the T cells are activated to fight the tumor but are sequestered from the tumor microenvironment or too few to affect tumor expansion. Another alternative, T cells can become “exhausted” following chronic exposure to the tumor antigen from persistent cancer. Lastly, T cells may remain anergic—unable to respond to stimuli—due to insufficient co-stimulation or dysfunctional state caused by self-antigen signals masking the response to tumor antigens. Understanding which of these T cell states dominates in the tumor environment of newly diagnosed MM patients may inform on the best method of overcoming barriers of disease relapse prior to relapse occurrence. The Newell lab investigated the status of T cells in newly diagnosed MM patients and published in Blood their findings that these patient’s T cells lacked markers of exhaustion AND evidence of tumor specificity.

A challenge in the field has been inconsistent features used to classify exhausted T cells, explained Dr. David Glass, a postdoctoral research fellow in the Newell lab. “It's difficult to prove a negative, so we asked, 'how would T cell exhaustion and a productive T cell response manifest in the data?' We then systematically demonstrated those features were absent by examining surface protein expression profiles, gene expression profiles, clonal dynamics, and responses to stimuli in patients' T cells. Here, we established that T cell exhaustion and a productive T cell response are not commonly found in patients with newly diagnosed multiple myeloma.” “Our findings may at first glance seem a bit unexpected, as T cell exhaustion or dysfunction is commonly observed in the presence of cancer,” continued first author Dr. Carolyn Shasha. “The absence of these exhausted cells implies that in newly diagnosed multiple myeloma patients, cancer immune evasion is not primarily due to the induction of a dysfunctional T cell response.” This means that the training of T cells may be key to effective tumor-specific killing.  

The specific mechanism of immune evasion employed by the tumor is critical to predict which therapeutic approaches should be employed. Dr. Glass explained, “Using an immunotherapy that reinvigorates a T cell response is unlikely to be successful in patients that never mounted a T cell response in the first place.” Therefore, these findings in MM patients emphasize prioritizing immunotherapies that stimulate a new T cell response (such as those targeting 'cold' tumors), explained Dr. Shasha. The researchers hope that their findings will encourage others to study MM immune evasion strategies and develop approaches that might counter or manipulate T cells for therapeutic benefit.

These findings raise additional questions pertaining to T cells in MM. The first is whether MM patients with relapsing disease—not newly diagnosed MM—will similarly lack markers of T cell exhaustion, or if this population of cells is enriched during disease relapse. “We are hoping to answer this question by applying the same single-cell multi-omic sequencing strategy to T cells from a cohort of patients with relapsed/refractory myeloma,” shared Dr. Glass. The second question is, if T cell exhaustion isn’t the key, then how are cancer cells evading detection by T cells? Dr. Glass explained that to address this question, they will employ spatial transcriptomics on bone marrow cores and investigate if the organization of the tumor microenvironment insulates tumor cells from detection.

“We are very proud that this work was the product of team science,” commented Dr. Newell. “We initiated this study through a collaboration with the Allen Institute for Immunology, which was initially led by Tom Bumol at the time and aimed to broadly assess immune profiles of healthy donors and patients longitudinally in a variety of settings and this is still ongoing.” This idea was supported by several Fred Hutch faculty members including Damian Green, Phil Greenberg, and Evan Newell. Support on initial planning was provided by Stan Riddell. While this project focused on the T cell response for longitudinal profiling of MM patients, broader analyses of these same patients and samples are a priority and currently underway, commented Dr. Newell.
 

The spotlighted research was funded by the National Institutes of Health, the Cancer Research Institute, American Society of Hematology, Canadian Institutes of Health Research (CIHR), the Allen Institute of Immunology, the Parker Institute for Cancer Immunotherapy, Fred Hutchinson Cancer Center New Development funds, the Andy Hill Endowment Distinguished Researcher CARE fund, and Defeat Myeloma.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Andrew Cowan, Philip Greenberg, and Evan Newell contributed to this work.

Shasha C, Glass DR, Moelhman E, Islas L, Tian Y, Chour T, Xu G, Szeto GL, Peng T, Song X, Wurscher M, Cowan AJ, Bumol TF, Torgerson TR, Greenberg PD, Green DJ, Newell EW. 2025. Hallmarks of terminal T-cell exhaustion are absent in multiple myeloma from diagnosis through maintenance therapy. Blood. blood.2024025655. Online ahead of print.