When the silence speaks: T-cell dysfunction in myeloma Free

In this issue of Blood, Shasha et al report that CD8⁺ T cells in newly diagnosed multiple myeloma (NDMM) do not exhibit transcriptional, phenotypic, or functional hallmarks of terminal exhaustion, challenging a prevailing paradigm that attributes immune evasion in cancer to T-cell dysfunction.¹ 

Despite remarkable recent therapeutic advances from T cell–based immunotherapies, relapse remains the rule rather than the exception for patients with MM.² Although T-cell exhaustion has been well described in many malignancies,³ its relevance in MM has been uncertain. Shasha et al here provide an unexpected conclusion: CD8⁺ T cells in NDMM lack the hallmarks of terminal exhaustion when monitored from diagnosis through maintenance therapy. Using a multiomic single-cell approach across longitudinal bone marrow (BM) and peripheral blood samples, the authors argue that the MM T-cell landscape is not exhausted, but enriched for naive, quiescent, or homeostatically activated T cells that lack evidence of prior tumor antigen engagement.

These findings are provocative and counterintuitive. In solid and hematologic malignancies as well as in chronic viral infections, tumor-infiltrating CD8⁺ T cells often display a canonical exhaustion signature, marked by clonal expansion, sustained PD-1 and CD39 expression, and functional hyporesponsiveness.^3-6 This phenotype is predictive of response to immune checkpoint blockade and is the rationale for T cell–targeted therapies.^5,6 Here, the authors found the opposite: the absence of such cells in both treatment-naive NDMM, despite tumor presence as well as immune perturbation, and cells from patients with MM on standard-of care treatment that, in theory, should provoke T-cell engagement.

Shasha et al argue that T cells in NDMM are not “tumor-experienced.” They find no evidence of antigen-driven activation or clonal expansion in the exhausted-like population and were unable to identify antigen-specific T cells using a panel of nonpersonalized myeloma antigens. Their data suggest that the dominant immune landscape in NDMM is not shaped by persistent antigen stimulation, but rather by cytokine-driven, homeostatic activation of CD8⁺ T cells, particularly in the periphery.

Indeed, as the authors point out, the absence of exhaustion does not equate to absence of tumor-reactive T cells. Such T cells may exist but remain functionally inert due to failed priming, lack of costimulation, or sequestration from antigen exposure.⁶ Prior studies have identified rare tumor-specific T cells with clonally expanded T-cell receptors (TCRs) in the BM of relapsed patients with MM that received immunotherapy, albeit at low frequency and without phenotypic markers of chronic stimulation.^7,8 This raises the possibility that MM evades immune detection not by inducing exhaustion, but by avoiding recognition altogether.

The findings of this report might benefit from some contextualization. First, the absence of terminally exhausted CD8⁺ T cells does not imply the lack of antitumor immunity. T-cell function exists on a spectrum, ranging from anergy and quiescence to epigenetically arrested dysfunction.^3,6,8 Tumor-specific T cells may remain undetectable if they are spatially excluded from tumor niches, inadequately costimulated, or suppressed by regulatory networks in the BM microenvironment. Each of these states could yield T cells that are neither activated nor exhausted, what might be termed “immunologically silent.”

Second, the attempted methodology to identify tumor-reactive T cells in this study needs to be considered. The authors used peptide-major histocompatibility complex (MHC) tetramer staining with a nonpersonalized panel of putative myeloma epitopes and detected no tumor-specific T cells by flow cytometry. Although technically demanding, this approach likely underestimates the frequency of bona fide tumor-specific T cells, given the narrow antigen selection and patient HLA heterogeneity. In contrast, recent studies using personalized antigen screens or antigen-agnostic T-cell assays have detected rare but potentially important tumor-reactive CD8⁺ clones in hematologic malignancies.^7,9 Thus, the apparent lack of antigen experience may reflect limitations in detection rather than absence of biology. One could liken this to the difference between a battlefield and a fog of war. In solid tumors, exhausted T cells are the battle-worn veterans, scarred but identifiable. In MM, the enemy may be hiding in plain sight, and the soldiers never fully deployed. Their successful identification and activation, however, could unlock potent and sustained immune surveillance.

The article opens up several interesting questions:

1. Where are the tumor-reactive T cells in MM? This study serves as a cautionary tale for using exhaustion signatures as universal biomarkers of tumor-reactive T cells. Antigen-specific T-cell phenotypes may be highly context dependent, particularly in tumors that reside in specialized immunologic niches.

2. Can these silent T cells be identified and awakened? The findings reinvigorate the search for technologies to prospectively detect tumor-reactive T cells that may underlie the potent antitumor activity of current immunotherapies. The failure of bulk MHC tetramer panels highlights a key limitation: antigen targeting in MM is highly individualized, and the tumor mutational burden is low.¹⁰ Personalized epitope prediction pipelines, paired with functional assays, may be essential to uncovering these elusive cells.

3. Is the myeloma T-cell landscape immutable, or does it evolve with disease and therapy? Perhaps most importantly, this study challenges the design logic of immunotherapy in MM. Immune checkpoint blockade may have failed because it presupposes a preexisting exhausted T-cell population that simply needs reinvigoration.^5,6 The absence of such a population in NDMM suggests that strategies aimed at priming the immune response, such as neoantigen vaccination, engineered TCR therapies, or bispecific T-cell engagers, may be more fruitful than attempting to rescue a response that was never initiated. In this regard, MM may represent a “cold” tumor not because of overwhelming suppression but due to immunologic ignorance. Just as therapies in solid tumors are evolving to transform cold tumors into hot ones, so too must immunotherapy in MM shift from checkpoint reversal to immune ignition.

In sum, this study underscores the importance of context in immunology: what is true for T cells in one tumor type may not hold in another. The absence of exhaustion in NDMM does not imply immune health, but rather a distinct, and perhaps more evasive, form of dysfunction. As we move toward more individualized immunotherapy, understanding the why behind immune silence in MM may be just as important as knowing how to break it.

Conflict-of-interest disclosure: The authors declare no competing financial interests.