Dissecting tumor-immune dynamics and radiotherapy response in oligometastatic prostate cancer.
Authors: Kamran Sophia C. , Otani Yukako , Qi David , Pompa Isabella R , Dzeng Richard , Pittie Rea , Chung Ella , Otani Keisuke , Wo Jennifer Yon-Li , Zietman Anthony L. , Reeves Patrick , Van Allen Eliezer Mendel , Efstathiou Jason A. , Miyamoto David Tomoaki 
Published: January 2024

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Background: Radiation therapy (RT) can improve survival in oligometastatic prostate cancer (OMPC) patients (pts). Reports implicate immune system contribution to both local tumor control and systemic regression of metastases. Understanding molecular and immune drivers of clinical responses in irradiated OMPC pts may elucidate mechanisms of RT-driven antitumor immune activity. Methods: Prospective samples from consented pts with OMPC (de novo/oligorecurrent) receiving RT included baseline (pre-RT) and 3 post-RT blood samples (RT end, 3-, 6-months). Peripheral blood mononuclear cells (PMBC) were obtained at each timepoint. PBMC sample barcoding and antibody labeling was performed prior to analysis by mass cytometry by time of flight (CyTOF). Data were debarcoded/analyzed using standard deconvolution/gating/clustering algorithms. Wilcoxon signed-rank tests identified longitudinal differences in comparison to baseline. P <0.05 denotes significance. Results: Between 2020-2022, 14 OMPC pts (56 samples) met inclusion criteria (2 de novo, 12 oligorecurrent). All received androgen deprivation therapy. De novo OMPC pts received simultaneous RT to the prostate, pelvis, and OM lesions. 6/12 oligorecurrent pts received simultaneous RT to a pelvic field along with OM lesions, while the remainder received RT to the OM lesions alone. Median follow-up was 17 months (r, 3-29). Four pts (28.6%) experienced recurrence (defined by PSA progression). Median time to recurrence after RT was 10.5 months. Significant differences in immune cell subsets after RT compared to pre-RT levels were identified by CyTOF analysis. CD4+ naïve cells peaked 6 months post-RT, while CD4+ effector memory (EM) cells peaked immediately post-RT (p=0.0012) and decreased to baseline levels at 3 months. CD4+ effector cells expressing TIGIT, OX40, ICOS, and CD69 were significantly more abundant immediately post-RT (p<0.05) compared to baseline. CD8+ cells expressing ICOS increased post-RT and were significantly increased at 6 months (p=0.03). In marked contrast to recurrent pts, non-recurrent pts exhibited increasing CD4+ T regulatory cells that peaked 6 months post-RT (p=0.04) and CD4+ EM cells that peaked post-RT (p=0.02). CD4+ effector cells expressing ICOS (p=0.01) and PD-1 (p=0.01) were both increased immediately post-RT, while cells expressing 4-1BB continued to increase and peaked 6 months post-RT (p=0.04). These changes were not observed or not significant in the recurrent population. Conclusions: Longitudinal immune cell subset changes can be observed after RT for OMPC. These data support immune activation, particularly immediately post-RT in non-recurrent pts, with some longitudinal changes lasting up to 6 months. Further analyses include TCR sequencing, inclusion of serum proteomics, and baseline genomic markers that may predict immune system activation and clinical outcomes.