Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (+/-3.93) years, who received salvage radiotherapy with a mean of 69.66 (+/- 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (+/- 55.82) months, were enrolled in this study. We evaluated by immunohistochemistry the intratumoral ((t)) and peripheral stroma ((p)) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3, or PD-1-positive cells on tumor samples taken at the diagnosis ((d)) and relapse times ((R)). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1(+) cells. Our analysis revealed that higher CD8(p,R+) and lower PD-1(R+) TIL scores correlated to a longer bPFS. Higher CD8(p,R+) and CCR7(t,R+) TIL scores and lower CD45(p,R+) and FoxP3(p,R+) TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

Cancer biology & therapy. 2016 Oct 28 [Epub ahead of print]

Valerio Nardone, Cirino Botta, Michele Caraglia, Elodia Claudia Martino, Maria Raffaella Ambrosio, Tommaso Carfagno, Paolo Tini, Leonardo Semeraro, Gabriella Misso, Anna Grimaldi, Mariarosaria Boccellino, Gaetano Facchini, Massimiliano Berretta, Gianluca Vischi, Bruno Jim Rocca, Aurora Barone, Pierfrancesco Tassone, Pierosandro Tagliaferri, Maria Teresa Del Vecchio, Luigi Pirtoli, Pierpaolo Correale

a Radiotherapy Unit, Department of Oncology , Siena University School of Medicine , Italy., c Medical Oncology Unit, Department of Clinical and Experimental Medicine , "Magna Graecia" University of Catanzaro , Catanzaro , Italy., d Department of Biochemistry , Biophysics and General Pathology, Second University of Naples , Naples , Italy., e Section of Pathology, Department of Medical Biotechnology , University of Siena , Siena , Italy., f Urogynechological Department , INT Fondazione "G. Pascale" Naples , Italy., g Department of Medical Oncology , National Cancer Institute, Aviano (PN) Italy.