Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8+PD‐1− tumor‐infiltrating T cells in PD‐L1‐enriched tumor microenvironment

• Published in: International journal of cancer 2021-07, Vol.149 (1), p.214-227
• Main Authors: Eissa, Ibrahim Ragab, Mukoyama, Nobuaki, Abdelmoneim, Mohamed, Naoe, Yoshinori, Matsumura, Shigeru, Bustos‐Villalobos, Itzel, Ichinose, Toru, Miyajima, Noriyuki, Morimoto, Daishi, Tanaka, Maki, Fujimoto, Yasushi, Sone, Michihiko, Kodera, Yasuhiro, Kasuya, Hideki
• Format: Article
• Language: English
• Subjects: Antigen-presenting cells; Antitumor activity; Apoptosis; Cancer; CD8 antigen; Cell death; C‐REV, HF10, CD8+PD‐1− T cells expansion; Dendritic cells; Herpes simplex; immune checkpoint inhibitors; Immunoglobulins; Infiltration; Lymph nodes; Lymphocytes; Lymphocytes T; Macrophages; Medical research; Metastases; Mucin; Oncolysis; oncolytic virus; PD-L1 protein; Spleen; Tumor microenvironment; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.33550

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a “cold” tumor into a “hot” tumor with high CD8+ T‐cell infiltration. CD8+ T‐cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD‐L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C‐REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD‐L1 expression in tumors in vivo as well as persistence of high PD‐L1 expression on antigen‐presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C‐REV treatment increased the abundance of activated CD8+PD‐1− tumor‐infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+PD‐1high TILs into the tumor was observed in the control group. Moreover, the difference in PD‐1 expression was observed only in tumors after treatment with C‐REV, whereas most CD8+ T cells in the spleen, tumor‐draining lymph nodes and blood were PD‐1‐negative, and this did not change after C‐REV treatment. In addition, changes in expression of T‐cell immunoglobulin and mucin‐domain containing‐3 and T‐cell immune‐receptor with Ig and ITIM domains were not observed on CD8+ TILs after C‐REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD‐L1‐enriched tumor microenvironment, by recruitment of CD8+PD‐1− TILs. What's new? CD8+ T cell infiltration into the tumor microenvironment is critical to the antitumor efficacy of oncolytic viruses. T cell activity, however, is blocked by interaction with programmed cell death protein‐1 (PD‐L1). Here, the authors show that canerpaturev (C‐REV), a promising oncolytic virus, both promotes CD8+ T cell infiltration and upregulates PD‐L1 expression on macrophages and dendritic cells in vivo. Most CD8+ T cells, however, were PD‐1 negative following C‐REV administration, and tumor‐infiltrating CD8+PD‐1‐ T cells persisted late after treatment. The results suggest that the appearance of CD8+PD‐1‐ T cells in tumors may be due to C‐REV‐induced tumor microenvironment remodeling.