Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies

Abstract

Anti-PD-L1 antibodies inhibit interactions between PD-L1 and PD-1 and interactions between PD-L1 and B7-1, thereby reinvigorating anticancer immunity. Although there are numerous ongoing clinical studies evaluating combinations of standard chemotherapies and anti-PD-L1 antibodies, irinotecan has not yet been investigated in this context so there is little information about its compatibility with anti-PD-L1 antibodies. Here we investigated the efficacy of anti-PD-L1 antibody in combination with irinotecan and the role of irinotecan in the tumor–immunity cycle in an FM3A murine tumor model. Despite a transient decrease in lymphocytes in the peripheral blood after irinotecan treatment, the antitumor activity of anti-PD-L1 antibody plus irinotecan was significantly greater than each agent alone. Irinotecan in combination with anti-PD-L1 antibody enhanced proliferation of CD8+ cells in both tumors and lymph nodes, and the number of tumor-infiltrating CD8+ cells was higher than either irinotecan or anti-PD-L1 antibody monotherapy. Irinotecan was found to decrease the number of Tregs in lymph nodes and tumors, and specific depletion of Tregs by anti-folate receptor 4 antibodies was found to enhance the proliferation of CD8+ cells in this model. In addition, irinotecan augmented MHC class I expression on tumor cells and concurrently increased PD-L1 expression on tumor cells and tumor-infiltrating immune cells. These results indicate that irinotecan may enhance the effect of T cell activation caused by anti-PD-L1 treatment by reducing Tregs and augmenting MHC class I–mediated tumor antigen presentation, and concurrent upregulation of PD-L1 expression can be blocked by the anti-PD-L1 antibody. These interactions may contribute to the superior combination effect.

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

“…FDA-approved in cancer, selumetinib in phase 3 FDA-approved in cancer [206] Topoisomerase inhibitors (e.g., topotecan [207,209], irinotecan [208], and etoposide [207] Microtubule stabilizers (e.g., paclitaxel [207,209] and vinblastine [207]) Cisplatin [207] All FDA-approved in cancer…”

“…In addition, immunochemotherapy combining IFNα and 5-fluorouracil treatment resulted in increased MHC-I expression via STAT1/2 activation in murine pancreatic cancer models [206]. Besides this, several topoisomerase inhibitors (e.g., topotecan, irinotecan, and etoposide), microtubule stabilizers (e.g., paclitaxel and vinblastine), cisplatin, and ionizing radiation elevate MHC-I surface expression, which is thought to be induced via NFkB stabilization and IFNβ secretion [207][208][209]. These studies indicate that cytostatic drugs may, besides direct induction of cell death, also be involved in decreasing tumor immune escape via upregulation of antigen presentation, thereby making these drugs interesting candidates for combination therapy to improve immunotherapeutic strategies in cancer.…”

<p>Refractory Metastatic Colorectal Cancer: Current Challenges and Future Prospects</p>

“…82 , 83 Irinotecan and anti-PD1 demonstrated an additive effect on tumor regression in mice. 84 Multiple clinical trials, mainly in the refractory setting, are now examining combinations with ICI ( Table 3 ). The risk of increased toxicity and impact on quality of life is paramount to document.…”

Anti-GD2 immunotherapy with the chimeric antibody ch14.18 for high-risk neuroblastoma

“…Влиянием химиотерапии на микроокружение опухоли и циркулирующие иммунные клетки также можно объяснить улучшение ответа на указанную комбинацию. Так, иринотекан модулирует иммунное микроокружение путем снижения Foxp3-позитивных регуляторных Т-клеток (Tregклетки) и миелоидных клеток-супрессоров и приводит к увеличению пролиферации продуцирующих интерферон-гамма опухоль-специфических CD8 + -T-клеток [59]. Низкие дозы темозоломида также снижают количество Treg-клеток [60].…”