PSGL-1 Immune Checkpoint Inhibition for CD4(+) T Cell Cancer Immunotherapy.

Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4+ T cells in numerous disease settings including cancer. PSGL-1 is highly expressed on T cells and can engage numerous ligands that impact signaling pathways, which may modulate CD4+ T cell differentiation and function. PSGL-1 engagement in the tumor microenvironment may promote CD4+ T cell exhaustion pathways that favor tumor growth. Here we highlight that blocking the PSGL-1 pathway on CD4+ T cells may represent a new cancer therapy approach to eradicate tumors.

DeRogatis JM ，Viramontes KM ，Neubert EN ，Tinoco R ... -  《Frontiers in Immunology》

PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells.

Chronic viral infections where the antigen persists long-term, induces an exhaustion phenotype in responding T cells. It is now evident that immune checkpoints on T cells including PD-1, CTLA-4, and PSGL-1 (Selplg) are linked with the differentiation of exhausted cells. Chronic T cell receptor signaling induces transcriptional signatures that result in the development of various exhausted T cell subsets, including the stem-like T cell precursor exhausted (Tpex) cells, which can be reinvigorated by immune checkpoint inhibitors (ICIs). While PSGL-1 has been shown to inhibit T cell responses in various disease models, the cell-intrinsic function of PSGL-1 in the differentiation, maintenance, and reinvigoration of exhausted T cells is unknown. We found Selplg-/- T cells had increased expansion in melanoma tumors and in early stages of chronic viral infection. Despite their increase, both WT and Selplg-/- T cells eventually became phenotypically and functionally exhausted. Even though virus-specific Selplg-/- CD4+ and CD8+ T cells were increased at the peak of T cell expansion, they decreased to lower levels than WT T cells at later stages of chronic infection. We found that Selplg-/- CD8+ Tpex (SLAMF6hiTIM3lo, PD-1+TIM3+, TOX+, TCF-1+) cell frequencies and numbers were decreased compared to WT T cells. Importantly, even though virus-specific Selplg-/- CD4+ and CD8+ T cells were lower, they were reinvigorated more effectively than WT T cells after anti-PD-L1 treatment. We found increased SELPLG expression in Hepatitis C-specific CD8+ T cells in patients with chronic infection, whereas these levels were decreased in patients that resolved the infection. Together, our findings showed multiple PSGL-1 regulatory functions in exhausted T cells. We found that PSGL-1 is a cell-intrinsic inhibitor that limits T cells in tumors and in persistently infected hosts. Additionally, while PSGL-1 is linked with T cell exhaustion, its expression was required for their long-term maintenance and optimal differentiation into Tpex cells. Finally, PSGL-1 restrained the reinvigoration potential of exhausted CD4+ and CD8+ T cells during ICI therapy. Our findings highlight that targeting PSGL-1 may have therapeutic potential alone or in combination with other ICIs to reinvigorate exhausted T cells in patients with chronic infections or cancer.

Viramontes KM ，Neubert EN ，DeRogatis JM ，Tinoco R ... -  《Frontiers in Immunology》

Editorial: CD4(+) T Cells in Cancer Immunotherapies.

González-Navajas JM ，Elkord E ，Lee J 《Frontiers in Immunology》

CDK4/6 inhibition promotes immune infiltration in ovarian cancer and synergizes with PD-1 blockade in a B cell-dependent manner.

Great progress has been made in the field of tumor immunotherapy in the past decade. However, the therapeutic effects of immune checkpoint blockade (ICB) against ovarian cancer are still limited. Recently, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6i) has been reported to enhance antitumor immunity in preclinical models. The combined use of CDK4/6i and ICB may be beneficial, but the effects of CDK4/6is on the tumor immune microenvironment and whether they can synergize with ICB in treating ovarian cancer remain unknown. Methods: In this study, we first assessed the antitumor efficacy of abemaciclib, an FDA-approved CDK4/6i, in a syngeneic murine ovarian cancer model. Then, immunohistochemistry, immunofluorescence and flow cytometry were performed to evaluate the number, proportion, and activity of tumor-infiltrating lymphocytes. Cytokine and chemokine production was detected both in vivo and in vitro by PCR array analysis and cytokine antibody arrays. The treatment efficacy of combined abemaciclib and anti-PD-1 therapy was evaluated in vivo, and CD8+ and CD4+ T cell activities were analyzed using flow cytometry. Lastly, the requirement for both CD8+ T cells and B cells in combination treatment was evaluated in vivo, and potential cellular mechanisms were further analyzed by flow cytometry. Results: We observed that abemaciclib monotherapy could enhance immune infiltration, especially CD8+ T cell and B cell infiltration, in the ID8 murine ovarian cancer model. Immunophenotyping analysis showed that abemaciclib induced a proinflammatory immune response in the tumor microenvironment. PCR array analysis suggested the presence of a Th1-polarized cytokine profile in abemaciclib-treated ID8 tumors. In vitro studies showed that abemaciclib-treated ID8 cells secreted more CXCL10 and CXCL13, thus recruiting more lymphocytes than control groups. Combination treatment achieved better tumor control than monotherapy, and the activities of CD8+ and CD4+ T cells were further enhanced when compared with monotherapy. The synergistic antitumor effects of combined abemaciclib and anti-PD-1 therapy depended on both CD8+ T cells and B cells. Conclusion: These findings suggest that combined treatment with CDK4/6i and anti-PD-1 antibody could improve the efficacy of anti-PD-1 therapy and hold great promise for the treatment of poorly immune-infiltrated ovarian cancer.

Zhang QF ，Li J ，Jiang K ，Wang R ，Ge JL ，Yang H ，Liu SJ ，Jia LT ，Wang L ，Chen BL ... -  《Theranostics》

Activin-A impedes the establishment of CD4(+) T cell exhaustion and enhances anti-tumor immunity in the lung.

Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A's function. In a translational approach, we validated activin-A's anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

Morianos I ，Tsitsopoulou A ，Potaris K ，Valakos D ，Fari O ，Vatsellas G ，Bostantzoglou C ，Photiades A ，Gaga M ，Xanthou G ，Semitekolou M ... -  《-》