مقاله انگلیسی رایگان در مورد واکسیناسیون با سلول های سرطانی اولیه کولون – الزویر ۲۰۱۹

Background: Colorectal cancer remains a leading cause of cancer-related mortality worldwide. Metastases to the liver are often present at initial presentation and will form in most patients during their course of disease. We have previously demonstrated that enhanced trafficking and activation of tumor-infiltrating lymphocytes in colorectal liver metastases (CRLM) may improve antitumor immune responses. Thus, development of novel mechanisms to increase lymphocyte infiltration and activation are needed to improve patient outcomes. Methods: CT26 murine colorectal cancer cells were treated with physiologic levels of the potent inducer of immunogenic cell death mitoxantrone (MTX). An in situ vaccine was created with treated cells in an established model of CRLM. Cells were evaluated by flow cytometry for cell cycle evaluation and calreticulin expression. Splenic and tumorinfiltrating lymphocytes were isolated for phenotypic studies. Results: MTX-treatment of colon cancer cells resulted in a sub-G1 peak, inhibition of G1 cell cycle progression, and increased G2/M cell fractions while simultaneously increasing dynamic exposure of calreticulin on the cell surface (P < 0.05). Vaccination with MTX-treated cells resulted in significant decreases in CRLM formation associated with increased tumorinfiltrating leukocytes that displayed increased expression of the T cell surface activation marker CD69. Conclusions: Vaccination with MTX-treated primary colon cancer cells enhances tumorinfiltrating lymphocytes and clinical responses in CRLM.

Introduction

Colorectal cancer remains one of the leading causes of cancerrelated mortality worldwide. Colorectal liver metastases (CRLM) are often present at the time of diagnosis and remain the most common site of metastatic disease.1 In selected patients, surgical resection of CRLM has improved long-term survival, but unfortunately only 10%-20% of patients are surgical candidates. Most stage IV patients with CRLM will be managed with palliative intent utilizing multidrug chemotherapy regimens. However, systemic chemotherapy has limited efficacy with many treatment-related toxicities.2 New therapeutic strategies are focusing on enhancing the antitumor immune response by attempting to drive increased numbers of tumor-infiltrating lymphocytes into the tumor microenvironment. Although this strategy has increased response rates in microsatellite instable colon cancers, which represent less than 5% of colon cancers, to date current immunotherapeutic strategies have been unsuccessful in achieving this goal for most colon cancers.3-6 Previous studies have documented that the presence of activated and proliferating T cells within primary colorectal tumors is associated with improved survival.7,8 In addition, we have previously demonstrated an association between increased T cell infiltrates and improved outcomes in patients with CRLM.9,10 Thus, enhancing the antitumor immune response may play a viable role in treating patients with advanced gastrointestinal malignancies, including colon cancer and CRLM. Although chemotherapy is traditionally linked to its immunosuppressive effects in treating cancer patients, emerging studies have demonstrated that selected chemotherapeutics may enhance tumor immunogenicity.11 Chemotherapy-induced immunogenic cell death (ICD) is characterized by the release and/or increased expression of defined damage-associated molecular patterns, including calreticulin (CRT),12-14 and we have previously demonstrated that induction of ICD in colon cancer cells can generate specific antitumor immunity in colorectal cancer.15 Therefore, chemotherapy agents not traditionally used in colon cancer but that may induce ICD could have potential for enhancing antitumor immunity in colon cancer patients.