T cell exhaustion markers in multiple myeloma patients are lower after physical activity intervention

Purpose There is compelling evidence that CD4+ and CD8+ T cells are dysfunctional in multiple myeloma, compromising their ability to control disease progression. Pre-clinical models suggest that exercise represents a non-pharmacologic means to reduce immune exhaustion, but no studies to date have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in multiple myeloma patients. Patients and Methods The current study includes 24 multiple myeloma patients who participated in a six-month physical activity intervention, consisting of supervised strength training (n=12) and unsupervised home-based walking arms (n=12). Comprehensive flow cytometry was utilized to assess the frequency of CD4+ and CD8+ T cells and subpopulations expressing the markers of exhaustion PD-1, TIGIT, TIM3 and/or LAG3. Ratios of exhausted to non-exhausted cell populations, and percentages of exhausted to total populations of the same lineage, were calculated for the baseline and final timepoints. Results Eighteen of 20 exhaustion measures were lower at the end of the intervention than at baseline, and several were significantly or borderline significantly reduced in the entire sample or in one of the arms. The entire sample saw improvements in the ratios of CD4+ TIGIT+ to non-exhausted CD4+ (0.7 [0.6] to 0.6 [0.4], p=0.04) and CD8+ PD1+ to non-exhausted CD8+ (1.8 [2.6] to 1.5 [2.0], p=0.06), and in total exhausted CD8+ as a percent of total CD8+ (72.9 [21.9] to 68.3 [19.6], p<0.01). Conclusions This pilot study suggests that physical activity induces changes in MM patients’ immune systems, potentially rendering a less exhausted T cell state. MicroAbstract The purpose of this study was to examine markers of immune cell exhaustion in multiple myeloma patients before and after a six-month physical activity intervention. Several markers of immune exhaustion were significantly lower after the intervention. These findings suggest that exercise could serve as a non-pharmacologic means to render a less exhausted T cell state in multiple myeloma, the treatment of which relies heavily on engagement of the immune system.