| الوصف: |
Decresased responses to immune checkpoint inhibitors (ICIs) in NSCLC are associated with low tumor mutational burden (TMB), impaired tumor antigen presentation, decreased baseline CD8+ T lymphocytes tumor infiltration and low PD-L1 expression in the tumor microenvironment (TME). One approach to augment the efficacy of ICIs in NSCLC is to enhance anti-tumor T cell responses by utilizing in situ vaccination (ISV) with professional antigen-presenting dendritic cells (DCs). In preclinical studies as well as a phase I clinical trial, we have shown that ISV with gene-modified DCs expressing CCL21 (CCL21-DC) promotes effector T lymphocyte infiltration into the tumor, PD-L1 upregulation, and systemic tumor-specific immune responses. We hypothesized that in situ vaccination with CCL21-DC could promote T cell priming and activation, thereby sensitizing non-responsive NSCLC tumors to ICI. Utilizing multiple syngeneic murine models of NSCLC with distinct driver mutations [KrasG12D/P53+/-/Lkb1-/- (KPL); KrasG12D/P53+/- (KP); and KrasG12D (K)] and varying TMB, we observed that CCL21-DC ISV synergizes with anti-PD-1 therapy resulting in the eradication of a subset of tumors. Evaluation of KPL tumors by flow cytometry and scRNA-seq revealed that combination therapy reprogrammed the myeloid compartment to be less immunosuppressive, and induced T cell infiltration, Th1 polarization, as well as the enrichment of stem-like TCF1+ T cells within the TME. Intratumoral (IT) CCL21-DC enhanced CD103+DC migration to the local lymph node as determined by flow cytometry. Addition of ICI to IT CCL21-DC resulted in enhanced T cell proliferation and INF-γ secretion within the TME and the spleen. Whole exome sequencing (WES) of tumors revealed immunoediting of tumor subclones after IT CCL21-DC and ICI combination therapy. Tumor rechallenge studies demonstrated the establishment of systemic tumor-specific immunity in a subset of mice that were cured of disease.In conclusion, tumor vaccination with CCL21-DC sensitizes immune-resistant murine NSCLC to anti-PD-1 therapy. Combination therapy enhances anti-tumor T cell responses, resulting in immunoediting of tumor subclones and the generation of systemic tumor-specific immunity. In an ongoing clinical trial, we are evaluating the safety and efficacy of ISV with CCL21-DC in combination with anti-PD-1, pembrolizumab, in patients with advanced NSCLC who have progressed on front-line therapy. Citation Format: Ramin Salehi-Rad, Raymond J. Lim, Linh M. Tran, Yushen Du, Camelia Dumitras, Tianhao Zhang, William Crosson, Jensen Abascal, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett. In situ vaccination with CCL21-DC sensitizes non-responsive murine NSCLCs to anti-PD-1 therapy and generates systemic tumor-specific immune memory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4206. |