Distinct role of CD8 cells and CD4 cells in antitumor immunity triggered by cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir system

• Published in: Cancer science 2023-08, Vol.114 (8), p.3076-3086
• Main Authors: Umegaki, Sho, Shirota, Hidekazu, Kasahara, Yuki, Iwasaki, Tomoyuki, Ishioka, Chikashi
• Format: Article
• Language: English
• Subjects: Antigen (tumor-associated); Antitumor activity; Antiviral Agents - therapeutic use; Apoptosis; Arginase; arginase 1; Cancer; CD4; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell death; Cell-mediated immunity; Cells; Chemotherapy; CTLA-4 protein; Cytotoxicity; Enzymes; Experiments; Flow cytometry; Foxp3 protein; Ganciclovir; Ganciclovir - pharmacology; Ganciclovir - therapeutic use; Genetic Therapy - methods; Herpes simplex; Herpes viruses; Humans; Immune system; Immunosuppression; Immunotherapy; Inflammation; Inflammation - drug therapy; Kinases; Laboratory animals; Lymphocytes T; MDSC; Metastases; Myeloid cells; Neoplasms - drug therapy; Original; ORIGINAL ARTICLES; Peptides; Simplexvirus - genetics; Simplexvirus - metabolism; TAM; Therapeutic targets; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Tumor cells; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15843

Immune cells can recognize tumor‐associated antigens released from dead tumor cells, which elicit immune responses, potentially resulting in tumor regression. Tumor cell death induced by chemotherapy has also been reported to activate immunity. However, various studies have reported drug‐induced immunosuppression or suppression of inflammation by apoptotic cells. Thus, this study aimed to investigate whether apoptotic tumor cells trigger antitumor immunity independent of anticancer treatment. Local immune responses were evaluated after direct induction of tumor cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir (HSV‐tk/GCV) system. The inflammatory response was significantly altered at the tumor site after apoptosis induction. The expression of cytokines and molecules that activate and suppress inflammation simultaneously increased. The HSV‐tk/GCV‐induced tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors. Therefore, the role of T cells after inducing tumor cell death was explored. CD8 T cell depletion abrogated the antitumor efficacy of apoptosis induction, indicating that tumor regression was mainly dependent on CD8 T cells. Furthermore, CD4 T cell depletion inhibited tumor growth, suggesting the potential role of CD4 T cells in suppressive tumor immunity. Tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion to elucidate this immunological mechanism. Foxp3 and CTLA4, regulatory T‐cell markers, decreased. Furthermore, arginase 1, an immune‐suppressive mediator induced by myeloid cells, was significantly downregulated. These findings indicate that tumors accelerate CD8 T cell‐dependent antitumor immunity and CD4 T cell‐mediated suppressive immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy. Tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors; CD8 T cells induced antitumor immunity, while CD4 T cells suppressed that immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy.