Improvement of PD-1 Blockade Efficacy and Elimination of Immune-Related Gastrointestinal Adverse Effect by mTOR Inhibitor

During the past decades, immunotherapy, especially the antibody-mediated immune checkpoint blockade (ICB) has shown durable tumor inhibition and changed the paradigm of cancer treatment. However, a growing body of evidence suggests that ICB treatment induces severe immune-related adverse events (irAEs), and the side effect even leads to the discontinuation of lifesaving treatment. Here, we found that ICB treatment induces colitis in melanoma patients and promotes the infiltration of CD8+ effector T cells into colitic lesions. Further transcriptomic dissection indicated the PI3K-AKT-mTOR pathway was highly activated in CD8+ effector T cells of colitic lesions. Moreover, we developed a mouse melanoma model to recapitulate the gastrointestinal toxicity of anti-PD-1 treatment in clinical settings. Anti-PD-1 treatment significantly contributed to the infiltration of CD8+ T cells, and correspondingly induced severe enteritis. Immunohistochemistry experiments showed that the PI3K-AKT-mTOR pathway of T cells was activated by anti-PD-1 treatment. Blockade of the pathway with mTOR inhibitor sirolimus not only inhibits tumor growth but also suppresses the T cell infiltration in colitic lesions. More importantly, combination with sirolimus and anti-PD-1 synergistically inhibits tumor growth via inducing the immunogenic cell death of tumor cells in vivo. In summary, our research demonstrated the principle of mTOR inhibitor and anti-PD-1 combinatorial therapeutic regimen, which provided a novel therapeutic strategy for irAEs in clinics.

Fibrinolytic nanocages dissolve clots in the tumor microenvironment, improving the distribution and therapeutic efficacy of anticancer drugs

Fibrin, one of the components of the extracellular matrix (ECM), acts as a transport barrier within the core of tumors by constricting the blood vessels and forming clots, leading to poor intratumoral distribution of anticancer drugs. Our group previously developed a microplasmin-based thrombolytic ferritin nanocage that efficiently targets and dissolves clots without causing systemic fibrinolysis or disrupting hemostatic clots. We hypothesized that the thrombolytic nanocage-mediated degradation of fibrin clots in the tumor ECM can lead to enhanced intratumoral drug delivery, especially for nanosized anticancer drugs. Fibrin clot deposition worsens after surgery and chemotherapy, further hindering drug delivery. Moreover, the risk of venous thromboembolism (VTE) also increases. Here, we used thrombolytic nanocages with multivalent clot-targeting peptides and fibrin degradation enzymes, such as microplasmin, to dissolve fibrin in the tumor microenvironment and named them fibrinolytic nanocages (FNCs). These FNCs target tumor clots specifically and effectively. FNCs efficiently dissolve fibrin clots inside of the tumor vessels, suggesting that they can mitigate the risk of VTE in cancer patients. Coadministration of FNC and doxorubicin led to improved chemotherapeutic activity in a syngeneic mouse melanoma model. Furthermore, the FNCs increased the distribution of Doxil/doxorubicin nanoparticles within mouse tumors. These results suggest that fibrinolytic cotherapy might help improve the therapeutic efficacy of anticancer nanomedicines. Thus, microplasmin-based fibrinolytic nanocages are promising candidates for this strategy due to their hemostatic safety and ability to home in on the tumor.

CD200 Blockade Modulates Tumor Immune Microenvironment but Fails to Show Efficacy in Inhibiting Tumor Growth in a Murine Model of Melanoma

CD200-CD200R pathway regulates immune responses and has been implicated in the pathogenesis of a number of cancer types. CD200 blockade is considered a strategy for immunotherapy of CD200-positive cancers such as melanoma. Thus, it is critical to understand the potential impacts of CD200 blockade in a more human relevant tumor model. In this study, we evaluated these issues using the CD200+ Yumm1.7 mouse melanoma model. Yumm1.7 cells bear Braf/Pten mutations resembling human melanoma. We found that Yumm1.7 tumors grow significantly faster in CD200R–/– mice compared to wild type mice. Analysis of tumor immune microenvironment (TIME) revealed that tumors from CD200R–/– or anti-CD200 treated mice had downregulated immune cell contents and reduced TCR clonality compared to tumors from untreated wild type mice. T cells also showed impaired effector functions, as reflected by reduced numbers of IFN-γ+ and TNF-α+ T cells. Mechanistically, we found upregulation of the CCL8 gene in CD200R–/– tumors. In vitro co-culture experiments using Yumm1.7 tumor cells with bone marrow derived macrophages (BMDM) from WT and CD200R–/– mice confirmed upregulation of macrophage CCL8 in the absence of CD200-CD200R interaction. Finally, we found that anti-CD200 therapy failed to show efficacy either alone or in combination with checkpoint inhibitors such as anti-PD-1 or anti-CTLA4 in inhibiting Yumm1.7 tumor growth. Given that CD200R-deficiency or anti-CD200 treatment leads to reduced T cell responses in TME, using blockade of CD200 as an immunotherapy for cancers such as melanoma should be practiced with caution.