Hypofractionated Short Course Radiation Treatment Results in Systemic Immune Activation and Upregulation of the PD-1/PD-L1 Exhaustion Axis: A Prospective Pilot Study in Early Stage Prostate Cancer Patients

Wong, J.K.; Macfarlane, Alexander W.; Devarajan, Karthik; Shulman, Rebecca M.; Alpaugh, R. Katherine; Burbure, N.; Hallman, M.A.; Geynisman, Daniel M.; Horwitz, Eric M.; Campbell, Kerry S.; Meyer, Joshua E.

doi:10.1016/j.ijrobp.2020.07.837

Cited by 7 publications

(10 citation statements)

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“…Finally, PD-L1 expression seemed increased on monocytes/DCs after short-course radiotherapy (p = 0.047; p = 0.031) [20].…”

Section: Studies On Circulating Immune Cellsmentioning

confidence: 96%

“…Few articles evaluated PD-L1 expression by tumor and/or inflammatory cells in blood samples of PC patients [11,14,16,20,23,45,54,64,87,88,91,96,97,101,147].…”

Section: Pd-l1 Expression In Blood Samples: An Overviewmentioning

confidence: 99%

“…Few studies provided some information about PD-L1 expression and data concerning circulating immune cells (Table 3) [20,45,54,87,88,96,97,101]. PD-1/PD-L1 blockade (not PD-L2) enhanced Staphylococcus Enterotoxin B-induced IL-2 production in HDs, shifting the antigen-induced cellular reactivity toward a pro-inflammatory Th1/Th17 response (increased IFN-γ, IL-2, TNF-α, IL-6, and IL-17; reduced IL-5, IL-13).…”

Section: Studies On Circulating Immune Cellsmentioning

confidence: 99%

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What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy

Palicelli

Bonacini

Croci

et al. 2021

JPM

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Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.

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“…Finally, PD-L1 expression seemed increased on monocytes/DCs after short-course radiotherapy (p = 0.047; p = 0.031) [20].…”

Section: Studies On Circulating Immune Cellsmentioning

confidence: 96%

“…Few articles evaluated PD-L1 expression by tumor and/or inflammatory cells in blood samples of PC patients [11,14,16,20,23,45,54,64,87,88,91,96,97,101,147].…”

Section: Pd-l1 Expression In Blood Samples: An Overviewmentioning

confidence: 99%

Section: Studies On Circulating Immune Cellsmentioning

confidence: 99%

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What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy

Palicelli

Bonacini

Croci

et al. 2021

JPM

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“…In particular, increasing attention has been paid to immunohistochemical biomarkers such as Programmed death-1 (PD-1) and its ligand PD-L1, evaluating their ability to predict the response to immunotherapy drugs. PD-1 and PD-L1 are type-I transmembrane glycoproteins encoded by the PDCD1 gene (located on chromosome 2) and CD274 gene (located on chromosome 9), respectively: they are present on the surface of various immune cells, and PD-L1 may be expressed by tumor cells (including PC cells) [ 2 , 3 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , …”

Section: Introductionmentioning

confidence: 99%

“…However, PD-L1 constitutive expression could also be induced by genetic alterations (such as PTEN loss) or activation of signaling pathways (intrinsic immune resistance); epigenetic regulators may also interfere with PD-L1 expression [ 4 , 6 , 8 , 9 , 10 , 11 , 12 , 13 , 24 , 58 , 71 , 125 , 126 ]. Limited data are available for PC [ 8 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , ...…”

Section: Introductionmentioning

confidence: 99%

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

et al. 2022

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Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.

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What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic–Pathologic Correlations

Palicelli

Bonacini

Croci

et al. 2021

Cells

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Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic–pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

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Hypofractionated Short Course Radiation Treatment Results in Systemic Immune Activation and Upregulation of the PD-1/PD-L1 Exhaustion Axis: A Prospective Pilot Study in Early Stage Prostate Cancer Patients

Cited by 7 publications

References 0 publications

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic–Pathologic Correlations

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