Research Article Pretreatment Immune Status Correlates with Progression-Free Survival in Chemotherapy- Treated Metastatic Colorectal Cancer Patients Kohei Tada 1,2,3 , Shigehisa Kitano 4,5 , Hirokazu Shoji 6 , Takashi Nishimura 7 , Yasuhiro Shimada 6 , Kengo Nagashima 8 , Kazunori Aoki 9 , Nobuyoshi Hiraoka 10 , Yoshitaka Honma 6 , Satoru Iwasa 6 , Natsuko Okita 6 , Atsuo Takashima 6 , Ken Kato 6 ,Yasuhide Yamada 6 , Naoyuki Katayama 2 , Narikazu Boku 6 , Yuji Heike 1,3 , and Tetsuya Hamaguchi 6 Abstract It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with unresectable metastatic colorectal cancer (MCRC). We therefore investigated the relationship between the pretreatment immunologic status of 40 patients with MCRC who planned to receive the first-line chemotherapy and their progression-free survival. Twenty-five immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSC) and effector memory T cells (T EM ), were measured by multicolor-flow cytometry. We divided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared progression-free survival of the two groups. Patients with high M-MDSC, low CD4 þ T EM , or low CD8 þ T EM quantities had significantly shorter progression-free survival (P ¼ 0.004, 0.005, and 0.002, respectively). Patients were classified into two prognostic groups based on numbers of adverse factors; having two or three adverse factors (n ¼ 21, 52.5%) was correlated with significantly shorter progression-free survival compared with none or one (n ¼ 19, 47.5%; P < 0.001). The presence of two or three adverse factors was an independent poor prognostic factor for progression-free survival (HR, 9.2; 95% confidence interval, 2.5–34.2; P < 0.001). These results provide evidence that pretreatment peripheral immune status can inform the outcome of patients with MCRC treated with first-line chemo- therapy. Cancer Immunol Res; 4(7); 592–9. Ó2016 AACR. Introduction Effector T cells in cancer patients respond to tumor cells. Cytotoxic CD4 þ or CD8 þ T cells recognize tumor-specific anti- gens or tumor-associated antigens and exert direct cytotoxic actions against tumor cells. Colorectal cancer was the first neo- plasia found to be under immune surveillance (1, 2). An increased quantity of tumor-infiltrating lymphocytes (TIL), CD3 þ cells, CD8 þ cells, and Th1 cells in surgically resected colorectal tumor specimens is associated with an improved prognosis (1, 3–11). In a more detailed analysis of the infiltrating T cells, the quantity of CD45RO þ cells (memory T cells) or effector memory (T EM ) cells in a colorectal tumor was shown to have strong prognostic significance after surgery (12, 13). However, it has not been determined whether the quantity of T cells or memory T cells correlates with the outcome of unresect- able metastatic colorectal cancer (MCRC) patients treated with systemic chemotherapy. Because of the limited opportunities for obtaining resected specimens in MCRC patients, TIL analyses are difficult to conduct, and thus alternative immunologic parameters for determination of prognosis are needed. Peripheral blood is easily obtained with little burden on patients. Our preliminary study, which quantified the immune cells in peripheral blood of patients with gastrointestinal cancer treated with a peptide vaccine, suggested that patients with a high quantity of memory T cells in peripheral blood at pretreatment had durable stable disease, whereas patients with a low quantity had early progressed disease (unpublished data). Memory T cells are subdivided into effector memory (T EM ) and central memory (T CM ) cells. The former play an important role in antitumor immunity (12, 14, 15). Therefore, we hypothesized that the quantity of T EM cells in peripheral blood might correlate with prognosis in patients with MCRC. Immune-suppressive cells, including myeloid-derived suppres- sor cells (MDSC), inhibit the activation and proliferation of effector T cells, such that the tumor can evade the host immune response. Large numbers of MDSCs are a poor prognostic factor 1 National Cancer Center Hospital,Tokyo, Japan. 2 Department of Hema- tologyand Oncology, Mie University Graduate School of Medicine, Mie, Japan. 3 Immunotherapy and Cell Therapy Service, St. Luke's Interna- tional Hospital,Tokyo, Japan. 4 Department of Experimental Therapeu- tics (ex. Phase I trial center), National Cancer Center Hospital,Tokyo, Japan. 5 Exploratory Oncology Research and Clinical Trial Center, Divi- sion of Cancer Immunotherapy, National Cancer Center,Tokyo, Japan. 6 Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. 7 Department of Gastrointestinal Medicine, Tokyo Jikei Medical University, Tokyo, Japan. 8 Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan. 9 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute,Tokyo, Japan. 10 Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).  Corresponding Author: Yuji Heike, St. Luke's International Hospital, 9-1, Akashi- Cho, Chuo-ku, Tokyo, 104-8560, Japan. Phone: 81-3-3541-5151; Fax: 81-3-5550- 7532; E-mail: heiyuji@luke.ac.jp doi: 10.1158/2326-6066.CIR-15-0298 Ó2016 American Association for Cancer Research. Cancer Immunology Research Cancer Immunol Res; 4(7) July 2016 592 Downloaded from http://aacrjournals.org/cancerimmunolres/article-pdf/4/7/592/2350659/592.pdf by guest on 19 August 2023