Toll-like receptors (TLRs) are expressed and play multiple functional roles in a variety of immune cell types involved in tumor immunity. There are plenty of data on the pharmacological targeting of TLR signaling using agonist molecules that boost the antitumor immune response. A recent body of research has also demonstrated promising strategies for improving the cell-based immunotherapy methods by inducing TLR signaling. These strategies include systemic administration of TLR antagonist along with immune cell transfer and also genetic engineering of the immune cells using TLR signaling components to improve the function of genetically engineered immune cells such as chimeric antigen receptor-modified T cells. Here, we explore the current status of the cancer immunotherapy approaches based on manipulation of TLR signaling to provide a perspective of the underlying rationales and potential clinical applications. Altogether, reviewed publications suggest that TLRs make a potential target for the immunotherapy of cancer.

The role of the immune system against coronavirus disease 2019 (COVID‐19) is unknown in many aspects, and the protective or pathologic mechanisms of the immune response are poorly understood. Pro‐inflammatory cytokine release and a consequent cytokine storm can lead to acute respiratory distress syndrome (ARDS) and result in multi‐organ failure. There are many T cell subsets during anti‐viral immunity. The Th17‐associated response, as a pro‐inflammatory pathway, and its consequent outcomes in many autoimmune disorders play a fundamental role in progression of systemic hyper‐inflammation during COVID‐19. Therapeutic strategies based on immunomodulation therapy could be helpful for targeting hyper‐inflammatory immune responses in COVID‐19, especially Th17‐related inflammation and hyper‐cytokinemia. Cell‐based immunotherapeutic approaches including mesenchymal stem cells (MSCs), tolerogenic dendritic cells (tolDCs) and regulatory T cells (Tregs) seem to be promising strategies as orchestrators of the immune response against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In this review, we highlight Th17‐related immunopathology of SARS‐CoV‐2 infection and discuss cell‐based immunomodulatory strategies and their mechanisms for regulation of the hyper‐inflammation during COVID‐19.

Chimeric antigen receptor (CAR) T-cell therapy is one of the cancer treatment modalities that has recently shown promising results in treating hematopoietic malignancies. However, one of the obstacles that need to be addressed in solid tumors is the on-target and off-tumor cytotoxicity due to the lack of specific tumor antigens with low expression in healthy cells. Placental alkaline phosphatase (PLAP) is a shared placenta- and tumor-associated antigen (TAA) that is expressed in ovarian, cervical, colorectal, and prostate cancers and is negligible in normal cells. In this study, we constructed second-generation CAR T cells with a fully human scFv against PLAP antigen andthen evaluated the characteristics of PLAP CAR T cells in terms of tonic signaling and differentiation in comparison with ΔPLAP CAR T cells and CD19 CAR T cells. In addition, by co-culturing PLAP CAR T cells with HeLa and CaSki cells, we analyzed the tumor-killing functions and the secretion of anti-tumor molecules. Results showed that PLAP CAR T cells not only proliferated during co-culture with cancer cells but also eliminated them in vitro. We also observed increased secretion of IL-2, granzyme A, and IFN-γ by PLAP CAR T cells upon exposure to the target cells. In conclusion, PLAP CAR T cells are potential candidates for further investigation in cervical cancer and, potentially, other solid tumors.

Chimeric antigen receptor (CAR) T cell therapy is one of the cancer treatment modalities that has recently shown promising results in treating hematopoietic malignancies. However, one of the obstacles that need to be addressed in solid tumors is the on-target/off-tumor cytotoxicity due to the lack of specific tumor antigens with low expression in healthy cells. Placental alkaline phosphatase (PLAP) is a shared placenta/tumor-associated antigen (TAA) that is expressed in ovarian, cervical, colorectal, and prostate cancers and is negligible in normal cells. In this study, we constructed second-generation CAR T cells with a humanized scFv against PLAP antigen, then evaluated the characteristics of PLAP CAR T cells in terms of tonic signaling and differentiation in comparison with ΔPLAP CAR T cells and CD19 CAR T cells. In addition, by coculturing PLAP CAR T cells with HeLa cells, we analyzed the tumor-killing function and secretion of anti-tumor molecules. Results showed that PLAP CAR T cells not only could eliminate the cancer cells but also increase their proliferation in vitro. We also observed increased secretion of IL-2, granzyme A, and IFN-γ by PLAP CAR T cells upon exposure to the target cells. In conclusion, PLAP CAR T cells are potential candidates for further investigation in cervical cancer and potentially other solid tumors.